69 - Malignant Pericardial Effusion
Editors: Shields, Thomas W.; LoCicero, Joseph; Ponn, Ronald B.; Rusch, Valerie W.
Title: General Thoracic Surgery, 6th Edition
Copyright 2005 Lippincott Williams & Wilkins
> Table of Contents > Volume I - The Lung, Pleura, Diaphragm, and Chest Wall > Section XIV - Congenital, Structural, and Inflammatory Diseases of the Lung > Chapter 81 - Pulmonary Complications of Cystic Fibrosis
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Chapter 81
Pulmonary Complications of Cystic Fibrosis
Susan R. Luck
Thomas W. Shields
Cystic fibrosis (CF) is an inherited disease of the epithelial tissues of exocrine glands. Ductal obstruction by thick secretions results in multiple organ dysfunction. Cystic fibrosis is the most common lethal genetic disease in the white population and is most commonly found in persons of Northern European ancestry. This autosomal recessive disease has an estimated incidence in the white population of 1 in every 2,000 live births; in blacks, the incidence is 1 in every 17,000 live births. Cystic fibrosis is virtually unknown in Asian populations. Although the frequency is approximately equal in male and female children, women and girls in the United States reportedly succumb at younger ages, especially after the age of 16 years. This gender-related discrepancy was not found by Hudson and Phelan (1987) in their review of a large CF population in Australia.
Specially dedicated CF centers throughout the world have increased patient survival and promoted research into all aspects of diagnosis and treatment. FitzSimmons (1993) summarized the data on 18,000 patients from the United States submitted to the Cystic Fibrosis Foundation registry in 1990 and compared the results with registry reports dating to 1969. The proportion of adult patients increased from 8% in 1969 to 33% in 1990. In 1990, most patients were younger than 15 years, but 33% were 18 years or older; more than 7% were 31 years or older. From 1969 to 1990, the median age of survival doubled from 14 to 28 years. The median age of survival of male patients in 1990 was 30 years, as compared with 25 years for female patients. The median age of CF patients continues to increase; however, FitzSimmons (1993) noted that 25% of patients still die before the age of 20.
The epithelial tissues of CF patients are impermeable to the passage of chloride ions, which normally are transported through channels in the apical cell membranes. The chloride channels are part of a complex membrane protein [cystic fibrosis transmembrane regulator protein (CFTR)] that is encoded by the CF gene. The structure of CFTR was first described by Riordan and associates (1989). Tizzano and Buchwald (1992, 1993) and Collins (1992) reviewed the subsequent research into the location and function of CFTR and mutant proteins. The CFTR structure includes two areas or domains that cross the cell membrane and serve as the channels. Binding of phosphorylating nucleotides, including adenosine monophosphate, to intracellular domains of the protein is essential for CFTR function. Using monoclonal antibodies against the CFTR molecule, Kartner and co-workers (1992) confirmed the distribution of CFTR in the epithelial cells of pancreatic ducts, reabsorptive ducts of sweat glands, intestinal crypts, and the submucosal glands of respiratory epithelia.
Quinton (1990) reviewed the research that delineated the mechanism of chloride ion transport. The absence of chloride absorption in the sweat tubules results in the retention of excessive amounts of chloride ions as well as sodium ions and water in the sweat. In the respiratory epithelia, chloride secretion is deficient, and the epithelial cells absorb more sodium than normal. Water passively follows the chloride and sodium ions into the cells, with dehydration of the mucus secretions. Knowles and associates (1981) showed that the cellular concentration of the chloride ions results in a more negative bioelectric potential difference across CF epithelia as compared with normal tissues. The resting transepithelial elective potential is elevated from the normal range of 25 to 30 mV to 55 to 90 mV in CF individuals. Some drugs, such as amiloride, selectively inhibit the sodium pump and thus may reduce the transepithelial potential to nearly 0 mV; on the other hand, the chloride flux response that is normally increased by antagonists such as isoproterenol is absent in individuals with CF.
CLINICAL MANIFESTATIONS AND DIAGNOSIS
The levels of sodium and chloride in the eccrine sweat of patients with CF are almost always elevated to three to six times normal, usually greater than 60 to 80 mEq/L. This abnormality is present from birth and persists without any relation to the severity of pancreatic or pulmonary disease.
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Hyponatremic collapse can occur after heat exposure and excessive sweating. Prior to 1989, the diagnosis of CF was confirmed by the demonstration of an elevated sweat chloride concentration in a patient with typical chronic pulmonary disease or pancreatic insufficiency or both. Now, genetic testing can identify patients with unusual variants of the disease who may have normal sweat chloride levels, as will be discussed. Strong and associates (1991) described the cases of two sisters who had progressive lung disease beginning in early adulthood and repeatedly normal sweat tests. They were homozygous for an unusual CF gene mutation.
The major clinical sequelae of CF and their approximate incidences are as follows:
Pancreatic insufficiency with malabsorption of fat and fat-soluble vitamins (85%)
Chronic pulmonary disease with bronchiolar obstruction and recurrent infection (eventually nearly 100%)
Azoospermia resulting from atrophy of the Wolffian duct structures with absence of the vas deferens
Meconium ileus (neonatal bowel obstruction from inspissated meconium) (15%)
Related conditions include poor weight gain, delayed sexual maturation in boys, absent or delayed menarche in girls, pancreatitis and glucose intolerance, and rectal prolapse. Women experience reduced fertility, possibly related to thick cervical mucus. Intussusception and meconium ileus equivalent, recurrent abdominal pain, and bowel obstruction are seen in older children and adults with hard, impacted stool. Biliary tract abnormalities include an increased incidence of cholelithiasis (as high as 25%), focal biliary cirrhosis, and portal hypertension (symptomatic in 5% to 10%). Severe liver disease may be unsuspected. Stern and colleagues (1980) reported that 8 of 61 patients who died with cor pulmonale had asymptomatic biliary cirrhosis.
Lanng and co-workers (1991) found a steady increase in the incidence of diabetes mellitus with advancing age. Diabetes occurred in 32% of adults older than 25 years, and another 23% had an abnormal glucose tolerance test. Finkelstein and colleagues (1988) reported diabetes mellitus in 7% of adults over 20 years of age; the onset of this complication was associated with accelerated clinical deterioration. Reisman and co-workers (1990), however, found no significant difference between diabetic and nondiabetic patients of comparable pulmonary and nutritional status. However, both Rosenecker (2001) and Koch (2001) and their coinvestigators presented evidence that insulin deficiency leads to a direct decline in pulmonary function and that in CF patients with diabetes mellitus, the percent predicted forced expiratory volume in 1 second (FEV1) is less in all age groups as compared with those without diabetes (Table 81-1). Thus, both of the aforementioned authors and their colleagues have concluded that the presence of diabetes is a strong determinant of severe lung disease and reduced survival in the afflicted patients.
Osteoporosis is regarded as a late symptomatic complication in adult CF patients, although low bone densities and fractures may occur in children. Aris and associates (1998) were able to obtain a history of fractures during childhood in 52.8% of 70 CF patients, and Henderson and Specter (1994) reported an incidence of 25.1% in 143 children; both of these incidences are well above the expected rate. Rib and vertebral compression fractures are the more common fractures. Bone densities (g/cm2) were found by Bachrach and colleagues (1994) to be 35% and 26% lower in both men and women with CF, respectively, than in normal persons. The mechanism of this occurrence is unknown, but Ott and Aitken (1998) note that the contributing factors to the lower bone densities seen in patients with severe pulmonary disease are malabsorption of vitamin D, calcium, and other nutrients; hypogonadism; inactivity; respiratory acidosis; and cytokines from chronic infection. Although severe problems are noted in only a minority of CF patients, severe osteoporosis with major kyphosis and vertebral fractures may contraindicate lung transplantation. Furthermore, as pointed out by Aris and co-workers (1996), any existing osteoporosis is made more severe after lung transplantation. Hypertrophic pulmonary osteoarthropathy and inappropriate antidiuretic hormone secretion may occur in CF, as in other types of chronic pulmonary disease. Although the initial description of CF by Anderson (1938) was that of a fatal disease of infancy, the symptoms may not be recognized or even manifested until the patient is an adolescent or adult.
Most CF patients develop chronic sinusitis. The maxillary and ethmoid sinuses are opacified in 90% to 100% of children older than 8 months; the frontal sinuses rarely develop. Most patients present with symptoms of nasal obstruction
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and purulent rhinorrhea between 5 and 14 years of age. Treatment is with oral antibiotics and nasal steroids. Ramsey and Richardson (1992) estimate that 20% of CF patients require surgical treatment. Nasal polyposis is commonly associated, although this may resolve by late adolescence. Lewiston and colleagues (1991) suggested that all CF patients who are candidates for lung transplantation should have operative drainage of the maxillary sinuses because they typically are contaminated with Pseudomonas aeruginosa and are a source of pulmonary infection. Zukerman and Kotloff (1998) believe intensive medical therapy is better than invasive procedures. This controversy continues to the present time. When lung transplantation is planned, some centers, such as Stanford, as reported by Vricella and associates (2002), perform operative drainage routinely, whereas the St. Louis group, as reported by Mendeloff (1998), does it only infrequently.
Table 81-1. Mean Value of Percent Predicted FEV1 in Cystic Fibrosis Patients | |||||||||||||||||||||||||||||||||||
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In 1958, Shwachman and Kulczycki introduced a scoring system for children with CF that quantitates the severity of clinical disease and accurately predicts the results of pulmonary function testing. Doershuk and colleagues (1964) revised this widely used system to apply to all patients. Four separate criteria of clinical status are evaluated by a detailed history and physical examination. Each is assigned an equal value of 25 points, with 100 representing a perfect score. These criteria include the activity level as compromised by respiratory symptoms, physical examination and an estimate of the effort required for breathing, nutritional status with consideration of deviation from ideal body weight, and chest radiographic findings. A score of 55 or less indicates severe disease.
ADULT AND ADVANCED DISEASE
Several groups, including Shwachman and colleagues (1977), di Sant'Agnese and Davis (1979), and MacLusky (1985) and Penketh (1987) and their associates, detailed the progression and treatment of this disease in adults. Huang and colleagues (1987) found that a poor Shwachman-Kulczycki (S-K) score, low weight percentile, and Burkholderia cepacia colonization were all indicative of a poor prognosis. Young adults with a clinical score of 65 to 75 had a median survival of 12 additional years. Pinkerton and co-workers (1985) compared the coping patterns of 200 adults with CF to those of a similar group with chronic end-stage renal failure. Even those CF patients who appeared to cope well had a high incidence of depression, self devaluation, and body image distortion. Shepherd and associates (1990) found that compared with healthy peers, adults with CF were less likely to be employed, had fewer years of education, and were more likely to live with parents. Interestingly, neither of these reports found a correlation between the level of physical health or pulmonary function and the degree of patient autonomy or psychosocial problems.
Long-standing hypoxia and lung infection eventually result in pulmonary vasoconstriction and fibrosis with a chronic increase in right ventricular afterload. The physical signs of right ventricular failure are overshadowed by those of extreme pulmonary disease. Weight loss is common even after the development of peripheral edema. Hepatomegaly and a murmur of tricuspid insufficiency develop. Ascites is rare. Most of the 60 patients with cor pulmonale reviewed by Stern and colleagues (1980) were completely disabled. Their mean survival after the diagnosis of this condition was 8 months; 80% had died by 12 months. These patients may benefit from salt restriction and diuretics, with supplemental oxygen at night. Moss (1982) outlined the diagnostic criteria for cor pulmonale in CF: an S-K clinical score of 40 or less, vital capacity of less than 60% of predicted normal, and the inability to raise arterial Po2 to 300 torr after breathing 100% oxygen for 10 minutes. Because the hyperinflated lungs surround the heart, cardiomegaly and right ventricular hypertrophy are absent or underestimated on the chest radiograph and electrocardiogram. Lester and co-workers (1980) correlated the echocardiographic abnormalities with the progression of cardiac decompensation and also with the S-K score.
Because lung transplantation has become a treatment option for selected patients, aggressive therapy may be offered to those previously considered preterminal. Mechanical ventilation preceded lung transplantation in 10 of 54 CF patients reported by Massard and associates (1993); 4 of these patients survived. The waiting period for a donor organ may be prolonged, and 20% or more accepted transplant candidates expired in the series reported by Whitehead (1991) and Shennib (1992) and their colleagues. The complex ethical considerations involved in balancing a rational acceptance of terminal disease and recommendation of aggressive treatment as a prelude to possible transplantation are well outlined by Fiel (1991) and Warner (1991). They describe a negative experience for both patients and families in many cases. Recommendations for palliative and supportive care or transplant referral should be made at a reasonable time before disabling disease intervenes. Kerem and associates (1992) studied nearly 700 patients followed over 10 years and assessed those factors predictive of mortality of greater than 50% in 2 years: an FEV1 of less than 30% of predicted value, an arterial Po2 of less than 55 mm Hg, or an arterial Pco2 greater than 50 mm Hg. When a patient has reached this level of disease, future treatment options should be discussed realistically.
GENETICS OF CYSTIC FIBROSIS
An explosion in research and knowledge about the genetics and molecular and cellular biology of CF has occurred since 1989. Rommens (1989), Riordan (1989), and B.-S. Kerem (1989) and their associates isolated and cloned the
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CF gene; identified and characterized CFTR, the protein product of the gene; and pinpointed the DNA sequence of the defective gene involved with most cases. The normal gene is composed of 250,000 nucleotide base pairs and is located on the long arm of chromosome 7 (7q31.3). Tsui (1992) reviewed the nearly 300 different gene mutations that had been reported to the Cystic Fibrosis Genetic Analysis Consortium, but this was only the tip of the iceberg. Over 1,000 mutations have been discovered so far, as noted by Kulczycki and co-workers (2003). The genotype-phenotype relationship is complex and is affected by pollution, smoking, bacterial infection, and malnutrition, as well as by various therapeutic agents.
One specific mutant allele ( F508) is found in 67% of patients and is the most severe genetic lesion for homozygotes, as reported by Kulczycki and associates (2003). The deletion of three nucleotides from the midportion of the gene causes the deletion of a single phenylalanine at position 508 of the protein. An affected individual will have two abnormal CF genes and may be homozygous or heterozygous for the F508 allele or for a non- F508 allele. Carriers of only one gene usually are asymptomatic; however, Davis and Vargo (1987), among others, documented increased airway reactivity and an increased incidence of wheezing in heterozygous parents of children with CF. Anguiano and associates (1992) investigated a group of 25 infertile men with bilateral absence of the vas deferens, none of whom had pulmonary symptoms. Thirteen were carriers for F508, and three had a F508/non- F508 genotype.
Seven other mutant alleles are fairly common. The F508 allele and those alleles whose DNA sequencing is known can be detected by specific DNA testing, allowing accurate detection of carriers and of patients who have atypical or minimally symptomatic disease. Such identification is difficult if the alleles can be identified only by their relationship to known DNA markers and with comparison to the DNA of affected family members. The F508 allele is the most common CF gene found in white patients of Northern European descent, especially Danish patients, and is found less frequently in Southern European, black, and Ashkenazi Jewish patients.
Kerem (1990b) and Kristidis (1992) and their associates have shown that different alleles appear to influence the clinical severity of disease, particularly of the pancreas. As noted, patients who are homozygous for F508 tend to have severe classic CF, and almost all have pancreatic insufficiency. As many as 10% of the non- F508 alleles, however, lead to a mild form of CF in which the patient has pancreatic function sufficient for normal digestion. These alleles appear to be dominant over F508. There is no good correlation of genotype with the degree of lung disease or liver disease. Neither B-S Kerem (1989) nor Santis (1990) and their colleagues could correlate pulmonary function testing with genotype unless the patients were subdivided according to pancreatic function. Gaskin (1982) and Corey (1988) and their colleagues have shown that individuals with pancreatic sufficiency tend to have better pulmonary function, perhaps on the basis of better nutrition.
The development of a cure for CF must involve the alteration of the mutant CFTR or the transfer of one normal CF gene into enough respiratory epithelial cells to overcome the basic cellular defect. Further delineation of the intracellular function of normal and mutant CFTR may accelerate because the protein has been purified and reconstituted in an in vitro system by Bear and colleagues (1992). New forms of treatment can be evaluated in the mouse models produced by Snouwaert (1992) and Dorin (1992) and their colleagues, in which the CFTR protein has been inactivated. Because CF is a recessive disorder determined by a lack of gene function, adding one normal gene to the nuclei of the appropriate cells should convert the cell to a carrier state and allow normal function. Only 5% of normal gene expression should be necessary.
The normal CF gene has been delivered directly into respiratory epithelial cells using adenoviruses and retroviruses as vectors. First, DNA material that allows the virus to replicate within the infected cell is removed, then, the foreign gene for CFTR production is inserted into the viral genome. Large quantities of the replication-deficient recombinant virus can be produced in cell culture. Rosenfeld and co-workers (1992) showed that CFTR protein is expressed within the airway epithelial cells of rats for up to 6 weeks after infection with an adenovirus vector. The adenovirus can transfer the gene into differentiated tissues that are not undergoing frequent cell division, but the effect on the respiratory cells may last only several weeks. Recombinant retroviruses have been used by Drumm and colleagues (1990) to transform cells in vitro to express normal CFTR channel function. Although the effect of retrovirus gene transmission is expected to be long lasting, only cells undergoing mitosis can be infected, and the retrovirus may activate oncogenes.
Zeitlin (1998) has classified the basic defect of CFTR into five categories:
Class I, complete absence of CFTR
Class II, defective protein folding and trafficking
Class III, defect in regulation of CFTR function
Class IV, chloride channel conduction defect
Class V, reduction in synthesis affecting CFTR promoter to reduce mRNA transcription
Examples of gene mutations, resulting defects, and possible general therapeutic modalities for these classes are listed in Table 81-2.
Some of the specific treatment regimens have been evaluated in phase I studies. Zabner and associates (1993)
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reported that adenovirus-mediated gene transfer via nasal insulation could transiently correct the chloride transport defect in the nasal epithelia of patients with CF. However, Ferrari (2002) and Griesenbach (2002) and their colleagues reported that such gene therapy was not reliable because of vector problems and the development of resistance. One of the many new strategies is the use of nonviral methods of gene transfer, which include naked DNA, lipid DNA complexes, and complexes of DNA with polycations that can carry the CFTR gene, as reported by Ziady and coinvestigators (2003). Many other methods are also being studied.
Table 81-2. Organization of Regular Mutations in Transmembrane Conductance in Cystic Fibrosis According to Defect and Therapeutic Modality | |||||||||||||||||||||||||||||||||||
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PATHOPHYSIOLOGY OF PULMONARY DISEASE
Pulmonary infection with Pseudomonas aeruginosa is the most significant clinical component of CF. Kerem and colleagues (1990a) documented the variable but persistent decline in pulmonary function that occurs after P. aeruginosa colonization of the respiratory tract. Pier (1985), Thomassen and co-workers (1987), and Berger (1991) reviewed the properties of this organism and its unique interaction with the human host. P. aeruginosa adheres to damaged or abnormal mucosa through specific interactions between bacterial adhesions and the cell surfaces. The mucosa may be damaged by early childhood infection with viruses, Staphylococcus aureus, and Haemophilus influenzae. Prober (1991) documented the importance of viral infection in the exacerbation of bacterial infection and decline in pulmonary function. The abnormally viscid CF secretions impede mucociliary clearance of bacteria.
Mucoid strains of P. aeruginosa predominate in CF infection. Noninvasive colonies of mucoid organisms are protected from the action of antibiotics, immunoglobulins, and neutrophils by an extracellular polysaccharide matrix (alginate). Complex interactions occur between the bacteria and the large numbers of antibodies, immunoglobulins, and neutrophils that are attracted to the site of infection. Both neutrophils and P. aeruginosa organisms release elastase and other proteolytic enzymes that are destructive to bronchial connective tissue. The deleterious effects of neutrophil elastase include stimulation of mucosecretory differentiation of respiratory epithelium with increased mucus secretion, destruction of structural fibers of the airway, inhibition of phagocytosis, and inactivation of antipseudomonal antibodies.
The concept of actual bronchial tissue destruction is supported by the laboratory and pathologic evidence assembled by Bruce and associates (1985). Uninhibited elastase activity is indicated by the increased urinary excretion of amino acid degradation products of elastin and by the presence of fragmented elastin fibers in the CF lung at autopsy. Chronic mucosal infection, excessive production of viscid secretions, and the progressive destruction of bronchial tissue are self-perpetuated in a vicious cycle as the inflammatory and hyperimmune response from the host continues unabated. Chemical evidence of this response is the hypergammaglobulinemia, increased numbers of immune complexes in sputum and serum, and the increase in circulating P. aeruginosa antibodies found in patients with progressively severe lung disease and clinical deterioration. Chest physiotherapy and postural drainage of secretions help reduce the load of inflammatory and proteolytic products. Antibiotic therapy can temporarily ameliorate infection but also undoubtedly helps select resistant and more virulent organisms.
Burkholderia cepacia has arisen as a virulent pathogen in the CF population during the past 20 years. The biology and multiple drug resistance of this bacterium have been detailed by Goldmann and Klinger (1986). Lewin and colleagues (1990) reviewed the course of patients colonized with this organism at several CF centers. Earlier clinical deterioration and death occurred in those who also had moderate or advanced lung disease. The presence of this organism presages a poorer outcome after lung transplantation, as documented by de Perrot and co-workers (2003). The Stanford group, as reported by Vricella and colleagues (2002), will only accept patients with colonization by B. cepacia for lung transplantation if the organism is found to be sensitive to at least two antibiotics on synergy testing. Fortunately, a smaller percentage of CF patients are colonized with this organism than with P. aeruginosa.
The gross and histopathologic findings of the CF lung reflect the effects of the cellular defect and chronic infection.
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Esterly and Oppenheimer (1968) noted that the earliest histologic changes appear in the tracheobronchial submucosal glands, which become obstructed and dilated. These glands are the main site within the airway for the expression of the CF cell protein. Thereafter, thick mucus obstructs bronchioles and bronchi in a scattered fashion throughout the lungs. Bacterial colonization and mucosal infection follow. Ciliated cells are destroyed as bronchial epithelium undergoes metaplasia, the submucosa is infiltrated by inflammatory cells with submucosal abscess formation, and adjacent lymphoid tissue proliferates. The proteolytic destruction of bronchial tissue results in fibrosis with weakening of the integrity of bronchial walls and progressive bronchiectasis. Bedrossian and co-workers (1976) showed that the incidence of bronchiectasis rises steadily after 1 year of age.
Tomashefski and colleagues (1986) analyzed and quantified these bronchiectatic changes. Airway volume as opposed to parenchymal volume is increased with progressive disease. The airway volume in the CF patient is 10% to 20% of the total lung volume, as opposed to 4% in the normal individual. This increased proportion of bronchial volume and the occurrence of cystic lesions is seen primarily in the upper lobes. Zach (1990) speculates that this difference may reflect a decrease in the clearance of secretions and their proteolytic contents from the upper lobes, perhaps because of a smaller excursion of the upper lobes during ventilation. Hamutcu and associates (2002) concur that in CF patients the inflammation is centered in the airways. There is a decrease in the small airway density (airways <2 mm/cm2) that occurs with increasing age, and the percentage of the smallest airways (airways <0.35 mm) is lower in patients with hypercapnia. The aforementioned authors speculate that the decreased airway density in older patients and the decreased properties of smallest airways in hypercapnic patients is caused by increased dilatation of small airways.
PULMONARY FUNCTION STUDIES
The wide spectrum in the degree of pulmonary dysfunction among different patients reflects the variable progression of airway disease. Wessel (1983) reviewed those measurements of lung volumes and pulmonary mechanics that provide an objective basis for long-term follow-up and assessment of the efficacy of specific treatment. Most children can cooperate with testing by the age of 5 to 6 years, and pulmonary function studies are performed at regular intervals thereafter. The early and scattered obstruction of peripheral airways causes predictable abnormalities in arterial oxygenation, pulmonary volumes and capacities, and airflow mechanics. The uneven apportionment of inspired gases and blood flow to the alveoli results in an increase in the alveolar arterial Po2 gradient and arterial hypoxemia. The normally ventilated areas of lung continue to maintain a normal carbon dioxide tension. An increase in carbon dioxide tension is a preterminal finding associated with cor pulmonale. Volume displacement spirometry gives measurable evidence of increased dead space ventilation and air trapping. Sensitive indicators of abnormal lung volumes are an increase in residual volume (RV) and in functional residual capacity (FRC). The ratio of residual volume to total lung capacity (RV/TLC) usually is increased and suggests air trapping. Vital capacity and TLC are decreased only in patients with moderate to advanced lung involvement who suffer the restrictive effects of lung destruction and fibrosis. Because early disease is confined to the small airways, maximum expiratory airflows are decreased initially only at small lung volumes. Therefore, the maximum expiratory airflow after expiration of 75% of vital capacity (Vmax75) and the average maximum expiratory flow during the middle 50% of vital capacity are more sensitive than the FEV and the FEV1.
Zach (1990) emphasized the complexity of advancing lung disease. The walls of the central bronchi, progressively weakened by proteolytic damage to connective tissue, are unstable. These bronchi can overdistend during inspiration in response to negative intrathoracic pressure and then collapse during expiration, especially if forced. The high flow peak of expiration corresponds to the emptying of distended central bronchi (a dead space effect). Severely compromised end-expiratory flow rates indicate peripheral airway flow in addition to any effect from now partially collapsed proximal bronchi. Patients with more severe disease may have a complex and variable combination of peripheral, partly bronchospastic airway obstruction and a central, primarily bronchiectatic, airway instability.
RADIOGRAPHIC FINDINGS
The earliest radiographic abnormalities are evidence of hyperinflation with flattening of the domes of the diaphragm and an increased anteroposterior diameter of the chest. Bronchovascular markings are prominent, especially in the upper lobes. Atelectasis of the right upper lobe, right middle lobe, or left lower lobe in infants and young children should suggest the diagnosis of CF. The chest radiograph of a patient with well-established disease reveals a diffuse cystic interstitial process with maximum involvement of the upper lung fields (Fig. 81-1). Brasfield and colleagues (1980) reported that the most frequently occurring abnormalities include hyperinflation, usually of the upper lobes; patchy linear and nodular densities, probably representing bronchiectasis or small peribronchial abscesses; and lobar segmental atelectasis (Fig. 81-2). Fellows and associates (1979) suggested that increasingly prominent densities may represent dilated bronchial artery collaterals. Apical blebs appear in older patients.
Chest radiograph scoring can predict pulmonary function in children. Rosenberg and co-workers (1992) also have shown a strong correlation between chest radiographs of
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adult patients and pulmonary function, especially the FEV1. Changes in the radiograph, however, lagged behind decreases in FEV1 over 5 years of follow-up.
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Fig. 81-1. Anteroposterior (A) and lateral (B) radiographs of a 12-year-old boy show hyperexpansion of the chest wall and depressed diaphragms from overinflated lungs. Linear and patchy densities are concentrated in a contracted right upper lobe. Note the normal heart size and the prominent pulmonary arteries. The vertebral column is osteoporotic. |
Schwartz and Holsclaw (1974) suggested that the differential diagnosis in an older patient with undiagnosed interstitial disease should include CF in addition to chronic bronchitis, sarcoidosis, histiocytosis X, tuberculosis or other granulomatous infection, and connective tissue disease. The impression of microcardia, seen late in the course of the disease, is related to extensive pulmonary overinflation. A normal-sized or small heart does not rule out cor pulmonale. Computed tomography (CT) can specifically delineate radiopaque lesions, particularly the extent and severity of bronchiectasis.
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Fig. 81-2. Nodular cystic changes (bronchiectasis and scarring) and linear densities are prominent in the radiographs of a 16 year old with more severe disease. |
COMPREHENSIVE TREATMENT
Intensive therapeutic and prophylactic regimens initiated in the late 1950s were targeted to control pulmonary secretions and avoid atelectasis, to treat and prevent pulmonary infection, and to ameliorate other medical problems affecting these patients. These measures have resulted in the current prolonged survival of many patients without halting the progressive course of the disease. Early and compulsive care can retard pulmonary damage for lengthy periods of time, and a better quality of life can be sustained in those persons with more advanced disease. Fick and Stillwell (1989), Stern (1989), and Fiel (1993) summarized the current approach to comprehensive and everyday management. Specific treatment now available or under active investigation includes regulation of transepithelial ion transport, mucolytic therapy, and amelioration of lung inflammation.
The mainstay of therapy is to encourage deep breathing and coughing, which efficiently mobilize secretions. Hofmeyer and colleagues (1986) reported that segmental postural drainage, chest percussion or vibration, breathing
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exercises, and active aerobic exercise, when feasible, all contribute to the mechanical removal of secretions. Active breathing exercises alone, although attractive to the older patient, do not appear to maintain pulmonary function. Reisman and colleagues (1988) have shown a deterioration over that expected in patients who omitted routine physiotherapy in favor of breathing exercises over a 3-year period. Zach and Oberwaldner (1987) state that the mechanical clearance of mucopurulent secretions and their load of antigens and proteolytic agents is as important as antibiotic therapy and that the beneficial effects are longer lasting. Mist or nebulization therapy can help thin the thick sputum and provoke coughing. Room humidification, especially at night, is recommended. In some cases, chest physiotherapy can be more effective if preceded by aerosol inhalation of a bronchodilator such as albuterol in those patients with demonstrable bronchial hyperreactivity. Bronchoscopy and bronchial lavage have been used to clean out accumulations of tenacious secretions in failing patients, but without sustained improvement. Stern and associates (1978b) stated the technique is indicated only for persistent lobar or segmental atelectasis. Associated respiratory tract lesions (sinusitis, nasal polyps, and hypertrophied tonsils and adenoids) should be treated as indicated.
New methods to alter the tenacious adherence of the respiratory secretions are under investigation. DNA, released by degenerating inflammatory cells, further increases the viscosity of mucus. Human deoxyribonuclease (DNAse), which can degrade the large DNA molecules into smaller strands, has been cloned and can be produced in large quantities. Hubbard and colleagues (1992) reported thinning of the sputum and improvement in pulmonary function testing in 16 CF patients after 1 week of aerosol treatments. Knowles and associates (1990, 1991) have improved hydration of the secretions by blocking sodium absorption and stimulating chloride secretion. Application of amiloride hydrochloride, a potassium-sparing diuretic, to the respiratory epithelium blocks both sodium and water absorption. When amiloride was administered in an aerosol to adult patients, the sputum became less viscid and the expected decline in pulmonary function over 6 months was not seen. The half-life of amiloride in the airway is only 40 minutes; the drug must be administered several times a day. The triphosphate nucleotides [adenosine triphosphate (ATP) and uridine triphosphate (UTP)] can stimulate a chloride channel not related to CFTR. These chloride secretogogues also improve secretions in patients but appear to work better after pretreatment with amiloride. Aerosol treatments with the mucolytic agent N-acetyl-L-cysteine have been recommended in the past, but this drug is an irritant and causes bronchospasm.
Hata and Fick (1988) and Mouton and Kerrebijn (1990) have reviewed current antibiotic therapy for pulmonary infection in CF. The prescription of suppressive oral antibiotics is controversial. Conventional treatment for exacerbations of infection has included carbenicillin or ticarcillin and an aminoglycoside. Piperacillin, another synthetic penicillin, has a lower sodium load. The renal clearance of aminoglycosides is increased in CF patients, and these drugs must be administered more frequently. Ceftazidime, a third-generation cephalosporin, is bactericidal for many gram-negative organisms, including some that are resistant to the aminoglycosides. Imipenem, a carbapenem antibiotic, has a broad spectrum of activity and is bactericidal for P. aeruginosa. This drug is administered with cilastin, which inhibits degradation of the drug in the kidney and possible renal damage. Ciprofloxacin, a fluoroquinolone, is active against Staphylococcus aureus and Haemophilus influenzae as well as P. aeruginosa. Oral, twice-daily administration is a great advantage. The hepatic clearance of theophylline and warfarin (Coumadin) is decreased by ciprofloxacin; the doses of these drugs must be carefully monitored. Ciprofloxacin is not approved for use in children. When frequent or prolonged courses are necessary, the drugs can be administered at home through a temporary peripheral catheter, a central venous catheter, or a subcutaneous port. Many of these antibiotics can be administered by aerosol, and this technique does not appear to accelerate the emergence of resistant organisms. Pseudomonas-specific immunoglobulin has been administered intravenously to patients by Winnie (1989) and Van Wye (1990) and their associates. In these limited clinical studies, they found significant improvement in pulmonary function during acute exacerbation of infection in patients with moderately severe lung disease.
The host inflammatory response to lung infection can be decreased with antiinflammatory drugs. Auerbach and colleagues (1985) reduced morbidity and reported an improvement in pulmonary function in 45 patients empirically treated with alternate-day steroids (2 mg prednisone per kg) for 4 years. On the other hand, Rosenstein and Eigen (1991) found an unacceptable incidence of complications, such as cataracts, growth failure, and glucose intolerance. However, a later multicenter study of 4 years' duration reported by Eigen and colleagues (1995) that used alternate-day dosing regimens of prednisone versus a placebo in 285 CF patients (aged 6 through 64 years) with mild to moderate lung disease found that a beneficial effect on lung function occurred in the prednisone-treated patients, especially in those patients colonized with P. aeruginosa. Although the aforementioned complications were observed, it was concluded that the benefit outweighed the adverse effects when the regimen was less than 24 months in duration. Konstan (1998) recommends the use of prednisone 1 mg/kg every other day for a limit of less than 2 years in patients with mild to moderate lung disease; therapy should be discontinued if no improvement in pulmonary function is noted after 6 months of treatment. Greally and co-workers (1994) suggest the use of a short course of prednisolone (2 mg/kg every day for 2 weeks tapered to 1 mg/kg on alternate days for 10 weeks) as an adjunct to the treatment of exacerbations of the disease; this regimen was shown to improve the
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FVC and FEV1 and was associated with a decrease in serum IgG and cytokine concentration when compared with the use of a placebo. The use of the inhaled route of dosage of steroids is still under investigation.
Ibuprofen inhibits the release of an inflammatory product, a leukotriene, from neutrophils; this drug was shown by Konstan and colleagues (1990) to ameliorate the inflammatory response to lung infection in a rat model. Konstan and associates (1995) reported that high-dose ibuprofen (20 to 30 mg/kg up to 1,600 mg twice a day) slowed the progression of pulmonary disease in mildly affected patients (FEV1 > 60% predicted), particularly in children aged 5 to 12 years. In adults, the occurrence of gastrointestinal bleeding, increased risk of hemoptysis, or renal toxicity may outweigh any benefit of the drug. Konstan (1998) further notes that there are no data to actually support the use of this drug in adults but that its use can be recommended in children, with mild reduction of their pulmonary function (FEV1 > 60% predicted). Unfortunately, to date, according to Oermann and colleagues (1999), both prednisone and ibuprofen are underutilized in the management of CF patients.
The primary natural inhibitor of neutrophil elastase in the lung is 1-antitrypsin. McElvaney and associates (1991) administered this agent as an aerosol to 12 CF patients and found that posttreatment bronchial lavage fluid had a greater bactericidal activity against Pseudomonas. Other antiinflammatory therapies for CF lung disease are listed in Table 81-3. Clinical trials are under way to evaluate these agents.
Many CF patients have positive skin tests to inhalant allergens, and some have asthmalike symptoms. An aerosolized bronchodilator, such as albuterol, should be prescribed for patients with wheezing if pulmonary function improves after a treatment. The empiric administration of steroids rests on the impression of a good clinical response. Aspergillus fumigatus frequently colonizes the respiratory mucosa of patients with CF, but invasive disease is uncommon. However, approximately 10% of CF patients develop evidence of hypersensitivity to the organism. Allergic bronchopulmonary aspergillosis (ABPA) should be suspected in those patients with asthma symptoms and progressive disease or recurrent exacerbations despite otherwise adequate therapy. Brown plugs may be expectorated. Hiller (1990) and Levy (2003), as well as Skov (2000, 2002) and Mastella (2000) and their associates, have reviewed the criteria for diagnosis as well as the management of ABPA. The criteria include eosinophilia, an increase in serum IgE and in IgE specific for A. fumigatus, and positive serum precipitins to A. fumigatus. These criteria can be demonstrated in most affected patients. Laufer and associates (1984) believed that ABPA probably plays a role in destructive pulmonary disease that steroids could prevent. Improvement is usually seen within 2 weeks, although repeat therapy may be needed. Antifungal drugs should be reserved for those patients with significant side effects from steroids or with uncontrolled symptoms.
Table 81-3. Antiinflammatory Therapies for Cystic Fibrosis Lung Disease | ||
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Patients who show unexpected clinical deterioration may have superimposed infection by mycobacterial organisms. Mycobacterium tuberculosis infections occur infrequently. However, it has been recognized that a variable number of CF patients will develop nontuberculous mycobacterial infections, which are now often referred to as environmental mycobacterial infections. Hjelte and colleagues (1990) reported six patients with sputum smears and cultures positive for these organisms. The most common infecting organism is one of the Mycobacterium avium complex (MAC), but infection with several of the rapid growers (i.e., M. abscessus and less commonly, M. fortuitum) has been reported by D. E. Griffith and co-workers (1993). Recently, Mendeloff (1998) recorded the identification of M. chelonae in one of his transplant patients. Antimycobacterial drug therapy is complicated, and care must be observed to prevent adverse drug interactions (see Chapter 87).
Pancreatic exocrine insufficiency prevents the normal absorption of long-chain fats and fat-soluble vitamins. Despite the administration of pancreatin-containing tablets, an increased caloric intake is indispensable for normal growth. The diet should be high in protein, with fat intake adjusted to individual tolerance. All patients should receive increased doses of multivitamins and water-soluble preparations of vitamin E. Vitamin K is given in the first year of life and thereafter for specific indications. Additional salt and fluid are advised during warm weather. Those with less pancreatic involvement exhibit better growth, less pulmonary disease, and prolonged longevity. Energy requirements increase as respiratory disease progresses. Fried and associates (1991) showed that the resting expenditure of energy is normal in patients with an FEV1 greater than 85% of
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predicted, but it increases in a curvilinear fashion as the FEV1 declines.
The importance of supplemental nutrition to the maintenance and recovery of pulmonary function has received increasing attention. Corey and colleagues (1988) found a difference in the median age of survival of CF patients treated in Boston (21 years) as opposed to Toronto (30 years), where nutritional management received priority. Both Levy (1985) and Shepherd (1986) and their colleagues reported that long-term enteral supplementation through a nasogastric tube, gastrostomy, or jejunostomy is associated with an improvement or stabilization of pulmonary function. They could not demonstrate a long-term improvement in pulmonary function in older patients.
SURGICAL EVALUATION AND INTERVENTION
Ten percent of young children followed by di Sant'Agnese (1953) in the 1940s and 1950s developed lobar atelectasis and bronchiectasis. Persistent lesions were resected. Operative intervention also was required during that period for staphylococcal pyopneumothorax, empyema, and lung abscesses, as reported by Anderson (1958), Holsclaw (1970), and Taussig and colleagues (1974). Holsclaw (1970) and Lester and colleagues (1983) noted that the rare large pulmonary abscess usually responds to prolonged antibiotic therapy and bronchoscopic aspiration (Fig. 81-3). Otherwise, pulmonary resection is indicated. Today, bronchiectasis rarely is localized and suitable for resection.
The focus of thoracic surgery has shifted to adolescents and adults whose major pulmonary complications are pneumothorax, hemoptysis, and pulmonary failure. Late sequelae of a pneumothorax, of a bout of hemoptysis, or of a specific type of treatment are impossible to predict in this disease. Any complication may precipitate a further decline in precarious pulmonary reserve, culminating in death a few months later from cardiorespiratory failure. Current recommendations are based on experience with relatively small numbers of patients, often accumulated over many years that bridge various advances in medical therapeutics. Treatment is neither randomized nor prospectively determined in any report; long-term follow-up is not always available.
Preoperative Preparation
A systematic evaluation of all involved organ systems is obtained. The results of previous pulmonary function and clinical scoring and a current echocardiogram are vital for estimation of operative risks and prognosis of long-term outcome. Appropriate studies should determine the presence of previously unsuspected portal hypertension, diabetes mellitus, gastroesophageal reflux, or cholelithiasis, which can complicate recovery. Specific preoperative measures include vigorous chest physiotherapy, systemic antibiotics based on current sputum cultures, correction of any coagulation deficits, and relief of stool impaction with enemas or oral polyethylene glycol-electrolyte solution or both. Full and maximal caloric support should be guaranteed by peripheral or central parenteral nutrition or enteral formula supplements.
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Fig. 81-3. A. A 17-year-old girl developed a multiloculated abscess after a prolonged pulmonary exacerbation of infection. B. The abscess had cleared with scarring 2 months later after antibiotic therapy. |
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Anesthetic Considerations
Most postoperative complications are respiratory and can be limited with appropriate care. Lamberty and Rubin (1985) reviewed 77 patients who underwent general anesthesia for various procedures. The long-term decline of pulmonary function was comparable with that expected in other patients at similar ages.
The pathophysiology of the disease must be considered in choosing anesthetic techniques. The ventilation-perfusion imbalance and pulmonary fibrosis lead to the slow diffusion of inhaled gases, including oxygen. Therefore, a prolonged anesthetic induction and emergence time are seen with inhalant agents. Intravenous induction should be used in all cases. Spontaneous respiration may depend on a hypoxic respiratory drive, and tidal volumes will decrease if spontaneous respiration is allowed under anesthesia. Assisted or controlled ventilation must be maintained through a cuffed endotracheal tube. Light nonnarcotic preoperative sedation and awaken extubation are mandatory. The postoperative respiratory drive is depressed by hyperventilation and hypocarbia. Many patients are prone to develop laryngospasm, bronchospasm, and paroxysmal attacks of coughing. Increased secretions continue to accumulate during the operation and require frequent endotracheal suctioning. Ketamine produces bronchorrhea and is contraindicated. Inspired air and gases must be well humidified during and after the operation. Karlet (2000) has recently updated the guidelines regarding anesthetic management.
A pulse oximeter, an end-tidal carbon dioxide monitor, an airway pressure monitor, and an arterial catheter provide useful data during and after the operation. Intravenous atropine is given at the time of induction. A nasotracheal tube should not be passed if the patient has extensive nasal polyps. Single-lung ventilation and fluid overload should be avoided. The use of nitrous oxide is contraindicated in the presence of a pneumothorax or large bullae. Hypoalbuminemia and aminoglycoside therapy may prolong the action of nondepolarizing muscle relaxants. At the conclusion of the procedure, all narcotics and muscle relaxants must be completely reversed.
Table 81-4. Incidence of Pneumothorax in Patients with Cystic Fibrosis | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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The patient should be thoroughly suctioned, awake, and coughing before extubation. Both Schuster and Fellows (1977) and Rich and associates (1978) found that prompt extubation was feasible in many cases. Robinson and Branthwaite (1984) electively ventilated all those in whom a delay in adequate spontaneous respiration was expected. Those patients who are extremely ill from malnutrition or liver disease are easily oversedated and have decreased tolerance for local anesthetics. Humidified oxygen is provided postoperatively. Chest physiotherapy should be resumed immediately. Postoperative analgesia by intercostal or epidural block is helpful.
Pneumothorax
Pneumothorax is the most common surgical complication of pulmonary disease in CF. A pneumothorax follows
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the rupture of subpleural air cysts through pleura weakened by the effects of chronic inflammation. Tomashefski and associates (1985b) identified three different pathologic types of air cysts in older patients with CF who were dying of pulmonary disease. All cysts occur more frequently in the upper lobes. Bronchiectatic cysts are the only ones large enough to be well defined on chest radiographs, but their thick collagenous walls would seem to prevent rupture. Smaller subpleural emphysematous cysts, which give the lung surface a bubbly appearance, are the likely site of pleural rupture. Interstitial air cysts located adjacent to interlobular septa may cause interstitial air dissection with pneumomediastinum. Di Sant'Agnese and Vidaurreta (1960), Lifshitz and associates (1968), and Holsclaw (1970) described pneumomediastinum and subcutaneous emphysema with and without pneumothorax in a few patients. Tomashefski and colleagues (1985a) reported that visceral pleura obtained from CF patients during pleurectomy for pneumothorax or at autopsy shows little difference from that of patients with spontaneous pneumothorax of other cause. Pleural elastic fibers overlying air cysts are disrupted and degenerated, probably a result of the action of neutrophil and bacterial elastase.
Pneumothorax commonly occurs in adolescents and adults with advanced pulmonary disease and severe airflow obstruction. By 1970, several groups had recognized the increased frequency and the attendant morbidity and mortality of this complication (Table 81-4). As older groups of patients are followed for long periods, the incidence of pneumothorax increases: from 12% of children older than 10 years of age to 20% of adults older than 20 years. McLaughlin and colleagues (1982) reported, however, that the occurrence of pneumothorax correlated better with clinical scoring and increasing pulmonary disease than with age. This complication is more common in boys and young men, perhaps because of their longer life expectancy.
Most patients cough and complain of chest pain, increased dyspnea, and, on occasion, mild hemoptysis. Chest radiographs often reveal bullous disease in the upper lobes and evidence of tension within the pleural space (Fig. 81-4). No predilection as to the side of occurrence is noted. Thirty percent to 50% of all affected patients eventually develop a pneumothorax on both sides. A potentially lethal tension pneumothorax may occur in up to 40% of cases. Almost every reported series describes a few patients who died with a tension or concomitant bilateral pneumothorax before treatment could be instituted. Associated mortality is high even in the patients who survive initial treatment. Thirteen percent of 72 patients with pneumothorax followed by Schuster and co-workers (1983) from 1969 to 1982 died during hospitalization for management of the initial episode even though the pneumothorax was under control at the time of death. Penketh and associates (1987) reported that 25% of 61 patients followed at the Brompton Hospital, London, from 1965 to 1983 died with a pneumothorax.
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Fig. 81-4. Radiograph of the same patient as in Fig. 81-1, now 14 years old. Note a left tension pneumothorax with hyperexpansion of the left hemithorax and mediastinal shift to the right. He was treated by pleural abrasion after emergency tube thoracostomy. A right pneumothorax occurred 1 year later, and a right abrasive pleurodesis was performed. |
Observation, needle aspiration, and closed tube thoracostomy were the methods of treatment used initially. Disappointing results have been reported (Table 81-5). Fifty percent to 80% of all episodes of pneumothorax observed or aspirated either fail to resolve or recur. The rate of failure or recurrence after closed tube thoracostomy is 30% to 75%. Full pulmonary expansion may require more than one chest tube. Even the insertion of multiple tubes does not guarantee sufficient pleural reaction to prevent a subsequent tension pneumothorax (Fig. 81-5). In autopsy studies, Boat (1969), Schuster (1983), and Tomashefski (1985a) and their associates were unable to correlate the numbers of chest tubes placed with the degree of pleural symphysis. Prolonged and multiple-tube thoracostomy decompression is painful, restricts ambulation, and impedes chest physiotherapy. Because resolution of the pneumothorax is delayed, the patient faces increasing anesthetic and operative risks.
Aggressive attempts to ensure the prompt formation of a pleural symphysis have been advocated in the past. If the patient might become a lung transplant candidate, however, extensive pleural adhesions should be avoided. Previous pleurodesis or pleurectomy is not an absolute contraindication to transplantation at most centers, but hemorrhage is inevitable when these lungs are mobilized. Noyes and Orenstein (1992) recommended treating recurrent pneumothorax in such patients through a limited thoracotomy or thoracoscopy with ablation of apical blebs (the most common source of pneumothorax). If transplantation does not appear indicated or possible, treatment alternatives include
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chemical sclerosis, pleural abrasion, and pleural stripping with or without the resection or oversewing of apical lung bullae.
Table 81-5. Treatment of Pneumothorax by Observation, Needle Aspiration, or Tube Thoracostomy | ||||||||||||||||||||||||||||||||||||||||||||||
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Chemical sclerosis with aqueous solutions of quinacrine or tetracycline has been used in a small percentage of the cases in most earlier series. The random instillation of variable amounts of sclerosant has produced inconsistent results, although each drug can create diffuse pleural adhesions when used in sufficient amounts. Quinacrine was used with moderate success in earlier series, but occasional severe toxicity with large doses was reported. Jones and Giammona (1976) and Boat (1969), Cattaneo (1973), Kattwinkel (1973), Stowe (1975), and Schuster (1983) and their colleagues together reported a successful resolution in 20 of 22 patients. Although this drug is not available commercially in liquid form, a hospital pharmacy can prepare a sterile solution from tablets. Janzing and associates (1993) resurrected this drug as a preferred sclerosant. They report that patients have less chest pain than with tetracycline.
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Fig. 81-5. A 15-year-old girl had recurrent right pneumothorax after the treatment of four previous episodes of pneumothorax by tube thoracostomy. Localized pleural adhesions have not prevented a tension effect with flattening of the right diaphragm. |
Effective chemical sclerosis with tetracycline depends on the total dose of instilled drug. Sahn and Potts (1978) showed that a solution of 35 mg/kg body weight consistently produced complete obliteration of the pleural cavity in rabbits, as opposed to a solution of 7 mg/kg, which produced early fibrinous adhesions but not long-term symphysis. This dose-related response may explain the recurrence of pneumothorax in six of seven patients reported by Schuster and colleagues in 1983 because they used small doses of the drug. The clinical acceptance of tetracycline as a sclerosant is limited by immediate and severe chest pain. Tetracycline hydrochloride is now unavailable in an intravenous form. A similar effect may be produced by two semisynthetic tetracyclines that are manufactured for intravenous administration: minocycline hydrochloride (Minocin, Lederle Laboratories, Wayne, NJ, U.S.A.) and doxycycline hyclate (Vibramycin, Roerig Division of Pfizer, Inc., New York, NY, U.S.A.).
Daniel and associates (1990) treated nine CF patients with pneumothorax by talc (dry USP pure talc) insufflation of the pleural cavity with thoracoscopy using regional or general anesthesia. This minimally invasive procedure was uncomplicated; no recurrences were reported. After the division of all pleural adhesions, approximately 2 g of sterile talc powder is insufflated under direct vision, thoroughly coating the pleural surfaces. Spector and Stern (1989) also
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described the use of talc in five patients, with no recurrence in the four survivors. This technique combines a high rate of pleural symphysis with minimal risks of patient discomfort or complications.
Table 81-6. Treatment of Pneumothorax by Pleurectomy or Abrasive Pleurodesis | |||||||||||||||||||||||||||||||||||||||||||||||||
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Lifshitz and co-workers (1968) first reported thoracotomy for pleural abrasion and apical bleb resection in children with CF. Extensive experience with both pleurectomy and pleural abrasion has accumulated since 1970 (Table 81-6). Morbidity and mortality are low, considering the depressed physical status of these patients. Even staged bilateral procedures have been performed successfully by most groups. The operation should be performed after stabilization of the patient, which may include emergency placement of a chest tube. The operative approach should include a limited incision that preserves the major chest wall muscles. Abrasive pleurodesis can be accomplished through a small axillary incision using a dry gauze or other sterile abrasive surface.
Flume (2003) reviewed the present-day treatment of pneumothorax and noted that surgical pleurodesis is preferred over chemical or talc pleurodesis; it presents, as a rule, less of a problem if lung transplantation is done in the future. Chest tubes are removed after the air leak has ceased and the lung is well expanded. Rich and colleagues (1978) believe that a stapled resection of apical blebs is contraindicated, because the noncompliant lung prevents adequate closure. Garske and associates (2002) have reported the successful use of the application of biological glue via a minithoracotomy. Immediate operative and anesthetic complications are uncommon. Pleurectomy carries a higher risk of hemorrhage than does abrasive pleurodesis. Patients with severe airflow obstruction or with cor pulmonale may survive the procedure, but Boat and associates (1969), Mitchell-Heggs and Batten (1970), and one of us (SRL) and associates (1977) reported that the mortality in 6 months is high. Atelectasis and recurrent pneumothorax were particularly devastating in the series described by Penketh and associates (1987); five of six patients with these complications died within 6 months. Spector and Stern (1989) favored pleurectomy as the most successful procedure; when performed in 57 patients, however, the procedure failed in 5% and pneumothorax recurred in 11%.
McLaughlin (1982), Rich (1978), and Stowe (1975) and their associates and Robinson and Branthwaite (1984) reported postoperative assessment of pulmonary function in limited numbers of patients. There is a minimal long-term decline over that expected on the basis of progression of the underlying lung disease. Seddon and Hodson (1988) found no significant differences in postoperative respiratory function, incidence of recurrence, or incidence of major complications in a group of 27 adults who had either an operative pleurodesis or a pleurectomy.
Ideal treatment would ensure rapid resolution of the pneumothorax, eliminate the possibility of recurrence, and incur the least morbidity and mortality. The following conclusions are warranted:
Pneumothorax occurs in patients with long-standing pulmonary infection and with severe and progressive airflow obstruction.
Bilateral occurrence of pneumothorax is high.
Any form of treatment is palliative, and no improvement in baseline status can be expected (although mortality increases when definitive treatment is delayed and pulmonary function is severely depressed).
Closed tube thoracostomy and chemical sclerosis are appropriate primary therapy for a patient who will not be a
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transplant candidate (talc poudrage and quinacrine sclerosis are both effective, and quinacrine can be instilled without a general anesthetic).Lung transplantation is more difficult in the presence of diffuse adhesions, and apical bleb ablation or resection should be recommended for any possible transplant candidate.
Hemoptysis
Hemoptysis, like pneumothorax, occurs in older patients with well-established lung disease. Enlarged bronchial arteries supply multiple bronchopulmonary anastomoses in areas of bronchiectasis or abscess, usually in the upper lobes. The frequently immediate arrest of hemoptysis by bronchial artery embolization confirms this source of bleeding. Initial massive hemoptysis (greater than 300 mL of blood loss per 24 hours) is first seen at an average age of 15 years and occurs in at least 8% of those patients surviving beyond the age of 15 years. Blood streaking of sputum may be observed for several years before the occurrence of massive hemoptysis. The most common precipitating event is an exacerbation in pulmonary infection, although such episodes may be difficult to distinguish from advancing pulmonary disease. Coagulopathy is uncommon. As a group, patients with massive hemoptysis do not appear to have a worse prognosis than those with a similar degree of lung disease who never bleed.
The natural history of untreated hemoptysis in CF patients has been documented at two large centers, but with differing conclusions and therapeutic recommendations. Holsclaw and associates (1970) described 19 patients treated between 1959 and 1969. Their patients had severe pulmonary disease, with an S-K score of 55 or less in 15 (79%) and an associated pneumothorax in 5 patients. In 6 patients, the initial attack was terminal. Five died within 1 month; 2 others died within 6 months. These authors concluded that this ominous complication with a 6-month mortality of 68% should be treated by early lung resection whenever feasible. On the other hand, all of the 38 patients reviewed by Stern and colleagues (1978a) stopped bleeding within 4 days and survived the acute episode; 17 (45%) did have recurrence of massive hemoptysis. Only 5 required blood transfusion. Without specific intervention, 14 (37%) survived longer than 5 years (1 for 20 years). The S-K score was the most accurate prognostic finding. All 5 patients with a score of less than 35 died, whereas 15 with scores of greater than 60 survived.
The dramatic onset of profuse bleeding, with the potential of asphyxiation and exsanguination, inspires a sense of urgency for definitive treatment. Levitsky and associates (1970) first reported emergency bronchial artery ligation and pulmonary resection (pneumonectomy) for hemoptysis in a CF patient. The series of Schuster and Fellows (1977) and Porter and co-workers (1983) detailed successful operative results. Some patients with poor pulmonary function may even improve temporarily because much of the bleeding and resected lung tissue is nonfunctional and has acted as a source of continuing sepsis. Swersky and co-workers (1979) tamponaded bronchial bleeding with Fogarty balloons placed through a bronchoscope in four patients. Profuse hemorrhage ceased in a man treated by Bilton and colleagues (1990) after intravenous infusion of vasopressin began. This drug may allow for immediate medical stabilization, but prolonged administration causes fluid retention and bronchoconstriction.
Selective bronchial artery embolization (BAE) is now the preferred treatment. Remy (1977), Uflacker (1985), and Tonkin (1991) and their associates, as well as Sweezey and Fellows (1990), accomplished long-term control of bleeding with minimal risk of serious complication (Fig. 81-6). Cohen and colleagues (1990) state this approach is appropriate for patients without severe hemoptysis but with bleeding that is chronic, slowly increasing, or that interferes with daily lifestyle and chest physiotherapy.
Angiography and embolization can be performed in virtually every patient through a transfemoral catheter using local anesthesia and mild sedation. The bronchial arteries may arise from the aorta at a sharp angle, inviting subintimal dissection by the catheter tip. Numerous patterns of bronchial artery anatomy are seen. Retrograde aortic flushing is minimized by the hand injection of small volumes of contrast media through a catheter tip well seated 2 to 3 cm within the bronchial arterial trunk. Contrast shunted through anastomoses with the pulmonary circulation may highlight the pulmonary veins, but the contrast medium rarely extravasates at the bleeding point. Nonionic contrast media are less toxic to the spinal cord, and the use of these agents should minimize the dangers of transverse myelitis. The visualization of spinal radicular branches is not an absolute contraindication to embolization, as the rare demonstration of the artery of Adamkiewicz certainly would be. Cohen and co-workers (1990) noted spinal arteries branching from bronchial vessels in 11 of 20 patients.
Pieces of absorbable gelatin sponge (1 to 3 mm in diameter) or beads of synthetic polyvinyl alcohol are aspirated into a tuberculin syringe and then slowly injected through the wedged catheter. The smaller emboli are injected first to occlude the most peripheral branches. Twenty to 100 fragments per artery are necessary for near-complete embolization. Blood is aspirated frequently between injections, confirming catheter position within the lumen. The embolization of each artery is concluded when approximately 90% of the peripheral runoff has been blocked. At this point, forward arterial flow is so slow that further injection may flush retrograde into the aorta. In some cases, multiple vessels must be embolized to control recurrent hemorrhage, a time-consuming procedure.
 |
Fig. 81-6. Radiographs of the same patient as in Fig. 81-2, who was admitted with hemoptysis of over 500 mL of blood and a recent history of increasing pulmonary disability. A. A selective injection of the right upper lobe bronchial artery shows dilation and tortuosity of the vessel. The site of hemorrhage was not identified. B. After embolization of the artery with absorbable gelatin sponge (Gelfoam), a repeat bronchial injection shows near-complete occlusion of the artery. The bleeding stopped after the procedure. |
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Immediate side effects include transient fever and chest pain. Distal aortic embolization has caused small intestinal gangrene and transient cerebral and extremity ischemia. Dysphagia and esophagobronchial fistula have been reported, as has unilateral hemidiaphragmatic paralysis.
The value of preangiographic bronchoscopy to guide specific bronchial artery embolization is doubtful because (a) most patients can determine the side of hemorrhage; (b) most bleeding comes from the upper lobes, and from the right more often than from the left; and (c) regardless of the actual site of bleeding, multiple vessel embolization is probably indicated whenever possible.
The technique of BAE stops acute hemorrhage in 80% to 100% of all patients. Revascularization and recannulization occur with time. Tomashefski and associates (1986) examined the lungs at autopsy of patients who underwent embolization. They found extensive transmural destruction of arterial walls with fibrous replacement and extrusion of particles of polyvinyl alcohol. Despite initial control of bleeding by embolization in 25 patients, Sweezey and Fellows (1990) reported an increase during the following 3 months in mortality from cardiorespiratory failure. With extended follow-up, severe bleeding recurred in almost 50% of the 19 patients who survived over 3 months. Nonetheless, most were free of hemoptysis for over 1 year. Embolization should be repeated if hemorrhage recurs.
The reports of Cipolli (1995), Brinson (1998), and Barben (2002) and their associates of 14, 18, and 20 CF patients, respectively, with mild to moderate hemoptysis treated by BAE mirror the results of many of the aforementioned series. Control of the bleeding initially was successful in 95% to 100% of the patients, although two or three BAEs were sometimes required. However, late recurrences (usually after 1 year) occurred in 45% to 57% of the patients. Nonetheless, Antonelli and colleagues (2002) recorded that over a 3-year period CF patients with hemoptysis treated by BAE had fewer recurrent episodes, had better Nottingham Health Profile (NHP) scores, and experienced a better quality of life than those not so treated. Subsequent angiography for recurrent hemoptysis should include the head, neck, and chest wall to search for unusual collateral supply. Cohen and colleagues (1992) reported one patient in whom collaterals of a right bronchial artery arose from the right and left thyrocervical trunks and from the right internal mammary artery.
Atelectasis and Bronchiectasis
Mearns (1972) and Schuster (1964) and their colleagues reviewed their respective series of children who underwent resection for bronchiectasis between 1947 and 1967. The median age was 6 years, and the predominant organism was Staphylococcus aureus. Most had localized disease in the right upper lobe (Fig. 81-7). The lower lobe and lingula
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were the sites involved on the left. Marmon and associates (1983) described nine older children operated on between 1969 and 1981. No operative complications or deaths were reported. The 14 patients of Smith and colleagues (1991) who underwent lobectomy (13) and pneumonectomy (4) had a predominance of right-sided lesions. A significant decrease in FEV1 was noted after operation, although subsequently these children required fewer hospitalizations. Those with a preoperative FEV1 of less than 30% did poorly. Symptomatic localized bronchiectasis is now seen less frequently. Lobar atelectasis is avoided or treated expeditiously in most patients. The disease seen in older adolescents and adults usually involves more than one lobe. Computed tomography provides a noninvasive technique to evaluate the entire lung field for extent and severity of disease (Fig. 81-8). If pulmonary resection is indicated, the intensive preoperative program outlined previously should be instituted.
LUNG TRANSPLANTATION
Cropp (1984), Scott (1988), and Jones (1988) and their associates reported the first cases of CF patients who underwent heart-lung transplantation (HLTx). Heart-lung, bilateral en bloc (BDLTx), and bilateral separate or sequential (BSLTx) transplantation have been successfully performed in the CF population, with similar results as others undergoing transplantation (see Chapter 95). Because of the paucity of cadaveric heart-lung in bilateral lung donors, Bisson (1994) and Starnes (1996) and their associates, as well as other investigators, have used bilateral pulmonary lobar transplants (LDLLTx) from two living donors. The left lower lobe and right middle and lower lobes are the lobes of choice. Starnes and colleagues (1996) reported on 38 recipients from 76 donors with no mortality and minimal morbidity. The early results of 1-year actuarial survival of 61% compare favorably with results from conventional cadaveric HLTx, BDLTx, and BSLTx. According to Zuckerman and Kotloff (1998), 61 such procedures had been performed as of November 1997. The average age of CF patients at the time of transplantation in an earlier series reported by Starnes and co-workers (1992) was 27 8 years of age.
 |
Fig. 81-7. A 9-year-old girl had a persistently productive cough despite intensive treatment. A. Radiograph shows the right upper lobe remained contracted with extensive cystic changes for 4 years. Peribronchial abscesses contain air fluid levels. B. An anterior projection pulmonary perfusion scintigram performed with technetium 99m albumin microspheres confirms the poorly perfused status of this bronchiectatic lobe. |
The selection criteria for consideration for transplantation in CF patients are patients with end-stage disease with probable death within 2 to 3 years. Women are more often candidates than are men. As noted previously, Kerem and coinvestigators (1992) suggest that an FEV1 less than 30% predicted, Po2 less than 55 mm Hg, and Pco2 greater than 50 mm Hg predict a 50% mortality within 2 years.
Zuckerman and Kotloff (1998) have listed what they consider to be the standard selection criteria for lung transplantation
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in CF patients (Table 81-7). Other factors, of course, such as frequency of hospitalization, presence of pulmonary hypertension, and progressive weight loss, as well as an unacceptably poor quality of life, must also be taken into consideration. Each transplant center may have additional criteria, such as acceptable hepatic and renal function, absence of or easily controlled diabetes, adequate bone density, no evidence of spontaneous fractures, and no panresistant bacterial flora.
 |
Fig. 81-8. CT demonstrates bilateral saccular bronchiectasis in multiple lung segments (worse in the lingula and right middle lobe) of a 17-year-old girl with increasing and now nocturnal cough that produced purulent secretions. The bronchi are surrounded by edema and inflammation. The hilar lymph nodes are enlarged. |
Unfortunately, many of these patients have chronic colonization of the lungs with P. aeruginosa, which is predictive of a 10% mortality within 1 year of transplantation; worse yet, a smaller number of transplant candidates have superinfection due to B. cepacia that, according to Aris and associates (1997), may result in a 50% mortality within 1 year of transplantation. De Perrot and colleagues (2003) reported a 37.3% mortality in the first year posttransplant in patients with positive B. cepacia cultures. B. P. Griffith and colleagues (1993) had earlier noted that in the presence of resistant bacterial organisms there was only a 40% 1-year survival versus an 84% survival in the absence of such infection. Of interest is the study of Snell and co-workers (1993), who noted a subset of transplant patients in whom a B. cepacia infection was not recognized until posttransplantation and in whom the mortality was 80%, versus 30% if the infection was identified preoperatively.
Table 81-7. Standard Selection Criteria for Lung Transplantation | ||
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The presence of Aspergillus is now thought not to be of great importance unless invasive aspergillosis occurs after transplantation. Paradowski (1997) and Kanj and colleagues (1997) believe the presence of saprophytic fungal infection is no different in CF patients than in other patients undergoing lung transplantation.
In addition to parenchymal infection, the presence of sinusitis, advanced liver disease, and osteoporosis can affect the eventual outcome to a greater or lesser degree. Sinusitis is best treated medically rather than by invasive procedures, although the Stanford group does not concur with this recommendation, as reported by Vricella and colleagues (2002). Severe liver disease must be treated by prior liver transplantation or by simultaneous lung-liver transplantation. Severe osteoporosis may adversely affect the outcome, and a marked degree of reduction of bone density and a history of multiple bone fractures, especially those of the spine, may preclude consideration of transplantation. Zuckerman and Kotloff (1998) have suggested the potential contraindications to lung transplantation in CF patients (Table 81-8).
The specifics of lung transplantation and the operative techniques are presented in Chapter 95. With CF patients, both septic lungs must be removed at the time of transplantation, necessitating HLTx, BSLTx, or LDLLTx. Bilateral en
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bloc double-lung transplants are rarely done at the present time in North America. The operative technique for HLTx was described originally by Reitz and colleagues (1982); it has been changed only slightly, as reported by Jamieson and associates (1984), since then. Currently, HLTx with transplantation of the CF recipient's heart to a second patient, as described by Yacoub and co-workers (1990), continues to be performed in the United Kingdom, where extensive experience with these patients has accumulated.
Table 81-8. Potential Contraindications to Lung Transplantation in the Cystic Fibrosis Patient | ||
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Early results with BSLTx through bilateral anterolateral thoracotomies connected by a transverse sternotomy have been published by Pasque (1990) and Kaiser (1991) and their associates. More recent reports by Egan (1998), Wiebe (1998), Vricella (2002), and de Perrot (2003) and their co-workers as well as by Mendeloff (1998) are summarized in Table 81-9. This technique is increasingly popular in the United States, Canada, and France. Advantages of this method are the avoidance of cardiopulmonary bypass (CPB) in most cases and excellent exposure of the pleural cavities; again, the Stanford group practice is different and CPB is used routinely. Apical adhesions are readily exposed, and hemorrhage is less of a problem. On the other hand, the bronchial anastomoses are more likely to become ischemic, and anastomotic stricture requiring further intervention is more common than with HLTx. Living donors and bilateral lobar transplantation have continued to be used by Starnes and associates (2003), with very good long-term results (see Table 81-9). Barr and colleagues (2001) have described in detail the selection and technique of harvesting and transplantation of the living-donor lobes.
Preoperative preparation varies slightly at each transplant center but can be briefly summarized as follows:
Immunosuppression is achieved with cyclosporine and azathioprine, methylprednisolone followed by prednisone tapered to a daily dose of 0.2 mg/kg, and muromonab-CD3 (OKT3) or rabbit antithymocyte globulin.
Discordant cytomegalovirus reaction between the donor and recipient is managed by a course of intravenous ganciclovir sodium.
Severe sinus infection is managed by medical methods or by surgery (bilateral maxillary antrostomies and tobramycin irrigations).
Antibiotic coverage is instituted as indicated by the most recent preoperative cultures.
The operation is carried out as described by each respective transplantation group. Cardiopulmonary bypass is used routinely in HLTx and LDLLTx and electively in BSLTx. After removal of the recipient's lungs, thorough flushing of the open airway and hemithorax is carried out with copious amounts of warm dilute povidone-iodine solution or with tobramycin solution. The donor lung is then implanted by the technique used at the given transplant center. Postoperative ventilator support varies in the numerous transplant centers, although in most lung transplant patients extubation is carried out as soon as possible. However, following LDLLTx, ventilator support is usually continued for 1 to 2 days, as reported by Starnes and associates (2003).
The postoperative care consists of the following:
Continuation of the immunosuppression, generally using a three-drug protocol of cyclosporine, azathioprine, and prednisone or other corticosteroid.
When ganciclovir sodium was used preoperatively, it is continued by oral administration and is also supplemented by the use of cytomegalovirus immune globulin.
Maxillary sinus infection is aggressively treated by medical therapy or by continued irrigation if maxillary antrostomies had been established preoperatively.
Antibiotic coverage is initially directed by the preoperative cultures but is adjusted by postoperative bronchial cultures and sinus isolates.
Possible postoperative rejection is monitored with bronchoscopy and biopsies according to the Standard Working Formulation of Lung Rejection, reported by Berry and associates (1990) for the International Society for Heart and Lung Transplantation, or one of its modifications as described in Chapter 95.
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Table 81-9. Survival of Patients with Cystic Fibrosis Receiving Lung Transplantation | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Postoperative complications include pneumonia, reperfusion injury, adult respiratory distress syndrome, postoperative bleeding, wound infection, bronchial anastomosis disruption or stenosis or both, acute rejection, acute renal failure, deep venous thrombosis, cerebrovascular events, and infection due to bacterial, viral, or fungal organisms. The overall incidence of these events varies from 6% to 20% in the reports of Mendeloff (1998) and of Vricella (2002), Egan (1998), and Wiebe (1998) and their colleagues. Another complication is the occurrence of distal intestinal obstruction syndrome (DIOS). Gilljam and co-workers (2003) noted DIOS to occur in 20% of 80 bilateral lung transplants in 75 patients. Ten patients had a single episode, eight of which occurred early in the postoperative period. Five patients had recurrent episodes. All but two were managed medically, while two required surgical treatment.
Thirty-day mortality from all causes is generally less than 2%, although in-hospital mortality varies between 4.9% and 6.3% (see Table 81-9). Long-term survival rates of 70% to 93.2% at 1 year, 44% to 77.4% at 5 years, and 46.9% to 48.1% at 10 years have been recorded by some of the most recent studies. These results are exclusive of those CF patients known to have panresistant B. cepacia infection preoperatively, in whom the 5- and 10-year survival rates were only 36.2% and 17.4%, respectively (see Table 81-9).
Patients with CF pose a number of specific postoperative problems. Because of poor absorption from the gastrointestinal tract, as pointed out by Scott and associates (1989), unusually large doses of cyclosporine (a lipid-soluble agent) must be given. Patients with CF often need two to three times as much cyclosporine as patients without CF. To improve the levels of cyclosporine, the drug is often given three times per day with exogenous pancreatic enzyme. Insulin-dependent posttransplantation diabetes is a part of the pancreatic insufficiency syndrome present in patients with CF. Corticosteroids exaggerate the diabetic syndrome during periods of rejection when high-dose pulsed steroids are administered.
Infectious complications decrease with time from transplantation but remain the most common cause of death during the first postoperative year. As with other transplant patients, obliterative bronchiolitis from chronic rejection is the limiting deterrent to long-term survival. In Vricella and colleagues' (2002) series, obliterative bronchiolitis accounted for 50% (8 of 16) of the late deaths. Bronchiolitis obliterans is not uniformly lethal, but it remains a serious problem because it affects approximately half of the long-term survivors of lung transplantation, according to Egan and associates (1998).
Survival of CF patients after HLTx is similar to that of survival after HLTx for other end-stage disease processes. As recorded by Barlow and co-workers (2000), the results are essentially the same as those achieved either by HLTx or BLLTx in end-stage CF patients. Likewise, similar results have been obtained by Starnes and co-workers (2003) with the use of LDLLTx, as noted previously. It should be pointed out that in Starnes and associates' (2003) report, there was no difference in the actuarial survival between the adult and pediatric living lobe recipients.
At the present time, bilateral sequential lung transplantation is most commonly used for adult patients in North America, although heart-lung transplantation is still used in the United Kingdom. The latter is also used in small, younger children to overcome the problems of performing two small bronchial anastomoses, as noted by M tras and coauthors (1993). The use of living donors is driven by the overall lack of numbers of cadaver lungs, as evidenced by a mortality of 30% or more of end-stage CF patients awaiting transplantation, as recorded by de Leval (1991) and Starnes (1992) and their associates, among others. Poor nutritional status is one of the major risk factors for death while awaiting transplantation.
CF does not recur in the transplanted lung. Wood and colleagues (1989) have shown normal bioelectric potential differences in the donor airway mucosa even as the upper airway continues to exhibit abnormal negative potential. Pulmonary function after HLTx and bilateral lung transplantation in patients with CF is improved over the preoperative morbid state; however, some of these patients, as noted, develop obliterative bronchiolitis with subsequent deterioration of FEV1 in the first year after transplantation. M tras and colleagues (1993) reported an increase in FEV1 from 25.5% of predicted before transplantation to 75% of predicted at 3 months after bilateral lung transplantation. This value increased to 95% of predicted at 6 months and then decreased slightly at 1 year because of the development of obliterative bronchiolitis. De Leval and associates (1991) reported that most patients achieved an FEV1 of 80% or more of predicted by 3 months after transplantation. Cooper and co-workers (1994) reported that the results of a 6-minute walk increased from 348 meters pretransplantation to 711 meters posttransplantation. The Po2 in these same patients averaged 48 before transplantation and 98 after transplantation.
Although these results are encouraging, obliterative bronchiolitis continues to be a frustrating problem after lung or heart-lung transplantation. Concerns that immunosuppression in these patients would cause overwhelming postoperative infection have proved unfounded. Although
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early and midterm results of HLTx and BSLTx for terminal CF are encouraging, the shortage of donor organs limits the potential of lung transplantation to have a significant impact on the quality of life and on survival for the majority of persons with CF.
CONCLUSIONS
Over six decades of persistent medical care and investigation have expanded the horizons of each child and adult with CF. Prolonged survival is possible for many, although the emotional and financial consequences of life-long therapy are formidable. Definition of the genetic and cellular basis of the disease is beginning to allow the development of specific preventive and therapeutic measures for lung injury. At the same time, lung transplantation can offer further prolongation of life and a better quality of life to some patients with end-stage lung disease. Despite these advances, pulmonary complications continue to occur in patients who will not be transplant candidates, usually when the effects of the disease are escalating. The patient is ill-served by procrastination of definitive management. The thoracic surgeon must be prepared to recommend an appropriate and well-defined approach to operative and angiographic intervention. The goal of Mearns and colleagues (1972) for the thoracic surgeon treating CF patients continues to hold true today: The aim of surgical treatment is to slow the progression of the disease, to prolong life, and, most important, to improve the quality of that life.
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