At the time of the evaluation, he was 159 cm tall and his body weight was 50 kg. Chest computed tomography (CT) scans showed bilateral bronchiectasis with peribronchial inflammation, pulmonary consolidation, and fibrosis. Areas of hyperinflation and marked parenchymal destruction were present bilaterally (Fig. 50.1). Lung scintigraphy showed a severe and bilateral deficit of perfusion with residual, irregular perfusion essentially limited to the lower lobe of the right lung.

Mild hepatosplenomegaly was diagnosed at the CT scan, but liver function tests were normal.

Respiratory function tests revealed a severe pulmonary obstructive disease: forced expiratory volume in 1 second (FEV₁) = 0.63 L/min (16% of predicted value) and forced vital capacity (FVC) = 1.69 L (39%). Arterial blood gas sample showed: pH=7.39, arterial oxygen partial pressure (PaO2) = 61 mm Hg and arterial carbon dioxide partial pressure (PaCO2) = 48.7 mm Hg with oxygen saturation (SaO2) = 90% (room air).

The electrocardiogram (ECG) was normal. The echocar-diography showed increased right ventricle dimension to the upper limit of normal values and mild tricuspid regurgitation. The right heart catheterization showed a cardiac output (CO) of 4.94 L/min, mild pulmonary hypertension with a mean pulmonary arterial pressure (MPAP) of 25 mm Hg and pulmonary vascular resistance of 408 dynes/s/cm⁵.

During the last year, while on the lung transplant waiting list, his lung function deteriorated because of recurrent pneumonias; he became O2-dependent, notwithstanding continuous appropriate therapy with antibiotics, bronchodilator β-adrenergic inhaled agent, pancreatic enzymes, and laxatives, together with correctly performed chest physiotherapy.

On the day of lung Tx, now 19 years old, he weighed 45 kg. He was tachypneic at rest despite oxygen therapy. Arterial gases analysis showed a PaO2/fraction of inspired oxygen (F_iO2) of 240 mm Hg and PaCO2 of 54 mm Hg with a SaO2 of 97%. Arterial invasive blood pressure (AP) was 140/80 mm Hg with a mean arterial pressure (MAP) of 100 mm Hg and heart rate (HR) of 90 beats per minute. The pulmonary catheter inserted preoperatively revealed a CO of 6 L/min with an increase in MPAP up to 33 mm Hg (PAP = 53/23 mm Hg). Only low doses of intravenous (IV) midazolam (1 mg) was administered as premedication. Before the induction of anesthesia, a thoracic peridural catheter (T4–T5 intervertebral space) was inserted for postoperative pain relief.

Definition

CF is the most common autosomal recessive disorder in Caucasian population, with a frequency of about one in 2500 livebirths.¹ It is caused by mutations in a 230 kb gene on chromosome 7 encoding a 1480 amino acid polypeptide, named cystic fibrosis transmembrane regulator (CFTR), which functions as a chloride channel in epithelial membranes.^2,3

The basic defect of CF is abnormal epithelial chloride and sodium transport resulting in increased electrolyte content of secretions and in altered transluminal potential difference.^4,5 At the results of the CFTR gene mutation, a defect in the secretory process for sodium, chloride, and water occurs across epithelia lining of the pancreas, lungs, sweat glands, intestine, biliary system, reproductive and respiratory tracts, and salivary glands. The aberrant properties of the chloride channel disrupt osmotic gradients and transluminal potential differences, resulting in abnormally viscid secretions and obstruction of organ passages⁶ (Fig. 50.2). The disease is a clinical spectrum of differing severity and patterns of organ involvement; however, increased life expectancy and the quest for a better quality of life increases the probability for anesthesiologists to encounter CF patients for complications of the disease or for unrelated surgery.^6,7,8

CF affects multiple organs in the body (Fig. 50.3). The abnormal sweat chloride, the pulmonary disease, and the pancreatic disease constitute the classic “diagnostic triad” for CF, although either the pulmonary or the pancreatic disease or both may be clinically inapparent early in life.⁹ The essence of CF is the chronic, suppurative, obstructive pulmonary disease that ultimately compromises the patient’s life quality. Shortly after birth, many patients with CF have repeated episodes of lung infection that incites an inflammatory response that is slow to recede: the persistent lung infection and inflammation becomes self-sustaining. The ongoing massive inflammatory response ultimately destroys the airways, impairs gas exchange, and may ultimately lead to death. The electrolyte transport defects of the CF airway could conspire to desiccate airway secretions that may lead to trapping of bacteria in the lung and reducing mucociliary clearance. These events results in repeated bacterial infection with recurrent episodes of pneumonia.¹⁰

Initially, the infant lung develops substantial small airway mucous plugging, inflammation infection, and progressive dilatation of small and large airways. As a result, children and adults develop peripherally hyperinflated lungs to compensate for the partial occlusion of the conducting airway, which fill with thick, mucopurulent exudates.¹¹ Bronchiectasis, a major abnormality through the course of CF, is characterized by airways with walls that are atrophic and cuffed with dense, fibroinflammatory infiltrate of lymphocytes, plasma cells, and macrophages.¹² As patients age, the airways begin to terminate in large, fibrous-walled cavities that at the visceral pleura are identified on radiographs as thin-walled cysts. These cysts are often the residual of necrotizing bronchocentric inflammation and progressive enlargement, as stenosis and mucostasis in the communicating airway function as a neck-valve to progressively trap the air in the cavity.¹³ Acutely infected bronchi progress to chronic bronchiolitis, then chronic stenosing bronchiolitis and bronchiolitis obliterans.¹⁴ Although emphysema is not a major component of early lung disease of CF, multiple areas of periseptal emphysema produce cysts or bullae, with accentuated interspersed interstitium in these areas.¹⁵

The earliest change in pulmonary function will result in increased air trapping, as demonstrated by decreased ratio of residual volume to total lung capacity, and changes in the maximal midexpiratory flow rates, which involve small airway disease.⁹ Later, the FEV₁ is reduced out of proportion to the lung volume, indicating an obstructive ventilatory defect. The FEV₁ continues to decline throughout the life of the patient, and it is the single best predictor of mortality. Once the FEV₁ has reached 30% of predicted, the 2-year mortality is about 50%, and so this level of FEV₁ is often taken as a threshold value for referring patients for evaluation for lung Tx, which is indicated in CF when there is progressive decline in a patient’s functional reserve.

Chest radiographs become abnormal early in the course of the disease. The typical stigmata of bronchiectasis (cystic changes, ring shadow, thickened airway wall) first appear in the upper lobe. Gas exchanges may be initially well-preserved into the course of the disease, whereas hypoxemia and later CO2 retention occur in a later stage. Chronic hypoxemia associated with advanced pulmonary disease may be associated with pulmonary hypertension and cor pulmonale.^16,17 This generally develops gradually, but can be precipitated acutely by infection or other physiologic stress. A progressive decrease in right ventricular ejection fraction with progressive pulmonary disease has been demonstrated in CF patients, although not universally, even in severe lung disease.¹⁸ Although right ventricular dysfunction is characteristic, left ventricular abnormalities or a generalized cardiomyopathy have also been reported.¹⁶

The major morbidity and mortality associated with CF are secondary to respiratory failure and chronic pulmonary infection.¹⁹ Airway hyperactivity is common and may be contributed to by the immune response to the prolonged and varied antigenic stimulus.^20,21 Serious respiratory complications include pneumothorax, emphysema, and hemoptysis from erosion of hypertrophic bronchial arteries, which supply the chronically infected lung. The place of pleurodesis in the management of recurrent pneumothorax has been reduced by the development of endoscopic procedures. Hemoptysis from erosion of bronchial arteries may be treated by embolization of bronchial arteries by experienced interventional radiologists.

Exocrine pancreatic insufficiency is present in about 90% of patients with CF. Pancreatic disease is thought to result from a reduced volume of pancreatic secretion with low concentration of bicarbonate (HCO₃^–).²² Without sufficient fluid and HCO₃^–, digestive proenzymes are retained in pancreatic ducts and prematurely activated, ultimately leading to tissue destruction and fibrosis. The pancreas secretes insufficient lipolytic and proteolytic enzymes for normal fat and protein digestion and absorption. The resulting malabsorption contributes to the failure to meet raised energy demands caused by the hypermetabolic state associated with endobronchial infection. These patients are considered “pancreatic insufficient.” Commonly, patients with severe pancreatic insufficiency have more severe forms of lung disease and high sweat chloride concentrations than those with better pancreatic enzyme production.²³ Because lung infections can lead to reduced appetite and vomiting, malnutrition is further enhanced, which exacerbates lung infection, leading to a vicious cycle of malnutrition and infection. Pancreatitis or pancreatic inflammation may occur in association with pancreatic insufficiency, and diabetes develops in 1% of children and 13% of adults with CF and pancreatic insufficiency.^24,25 Diabetes in patients with CF shares features of the type 1 and 2 disorder, and a combination of reduced and delayed insulin secretion with insulin resistance is present in most patients.^26,27 It has the pattern of intermittent hyperglycemia, not associated with ketosis, which responds to insulin.²⁸

CF has a profound effect on multiple segments of the gastrointestinal tract. Manifestations range from meconium ileus in the newborn infant to the distal intestinal obstruction syndrome that occurs in older children and adults. Most of the manifestations are related to insufficient secretion of pancreatic enzymes, diminished secretions from mucous glands, and the resultant viscid and adherent intestinal content.

Symptomatic liver disease is an uncommon complication of CF²⁹; whereas a characteristic liver lesion of CF is focal or multilobular biliary cirrhosis, other manifestations include cholestasis secondary to common bile duct obstruction with inspissated bile, fatty infiltration of the liver, and, rarely, neonatal hepatitis.³⁰

Important components in the management of CF are: (1) nutrition; (2) correction of organ dysfunction, including clearance of airway secretions, antibiotic therapy, and replacement of pancreatic enzymes; (3) genetic therapy; and (4) organ transplantation. Because the major morbidity is related to bronchial and bronchiolar disease with resultant obstructive pulmonary disease (which accounts for >90% of mortality), most therapies focus on direct antiinflammatory treatment to prevent host-mediated inflammatory obstruction, direct treatment of Pseudomonas aeruginosa infection, and clearance of airway secretions by overcoming the viscoelastic properties of the abnormal mucus. Respiratory therapy includes postural drainage, forced expiratory technique, bronchodilator therapy, and inhaled β-adrenergic or anticholinergic agent to improve the expiratory flow rate. Clearing the airways of tenacious, purulent secretions has been an important component of CF therapy. Postural drainage with chest percussion and vibration, applied manually or with a mechanical percussor, are the “traditional chest physiotherapy.”³¹ The combination of increased caloric demand at baseline, the added caloric demands of chronic lung disease, the difficulty sustaining caloric uptake because of malabsorption in patients who are pancreatic-insufficient, and anorexia. For CF patients with active lung inflammation, it may be very difficult to sustain a normal weight for height.³²

Organ Transplantations

Until the advent of organ transplantation for patients with CF in 1984, for the majority, the inevitable outcome was death from overwhelming pulmonary sepsis. The availability of transplantation has profoundly altered the emphasis of care, and then, after transplantation, the quality of life for CF patients.^33,34

Today, when medical treatment is failing and a patient is listed for transplantation, there is an imperative to keep the patient not only alive, but also in optimal clinical condition. The optimal perioperative management of patients with CF requires an understanding of the relevant pathophysiology and the unique challenges presented by these patients.³⁵ A poorly nourished, bedbound, demoralized patient is unlikely to survive the rigors to transplantation. In patients awaiting lung Tx, mechanical ventilation and extracorporeal membrane oxygenation (ECMO) are often the last ways to create a bridge to lung Tx. Both interventions are associated with a poor posttransplant outcome and survival rate. To improve the results of these patients, new “bridging-strategies” are necessary. The concept of “awake venovenous-ECMO” is feasible for the treatment of CF and can be used as a “bridging therapy” to lung Tx.³⁶

It is an evident paradox that CF patients are listed for transplantation because they are unlikely to live for longer than 2 years, and yet must be presented for a lifesaving or life-threatening operation in the best possible health. The progression of pulmonary sepsis with Pseudomonas aeruginosa is relatively at a slow, which usually leaves sufficient time to list for transplantation the CF patient who is becoming unresponsive to treatment in a setting of multidisciplinary care. Occasionally, pulmonary sepsis will progress rapidly, and this is more commonly associated with infection with Burkholderia cepacian.³⁷

At the end of 2018, the U.S. Food and Drug Administration approved Trikafta (elexacaftor/ivacaftor/tezacaftor), the first triple combination therapy available to treat patients with the most common CF mutation. Trikafta is approved for patients 12 years and older with CF who have at least one F508del mutation in the CFTR gene.³⁸

Trikafta is a combination of three drugs that target the defective CFTR protein. It helps the protein made by the CFTR gene mutation function more effectively. Trikafta increases in the percent predicted FEV, known as ppFEV₁, which is an established marker of CF lung disease progression. It also results in improvements in sweat chloride, number of pulmonary exacerbations (worsening respiratory symptoms and lung function), and body mass index (weight-to-height ratio) compared with placebo.^39–43

Currently available therapies that target the defective protein are treatment options for a limited number of patients with CF because many patients have mutations that are ineligible for treatment.

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