Kendra J. McAnally & Stephen P. Kantrow

OBJECTIVES

Recognize lung injury caused by common therapeutic drugs and substance abuse.

Identify the pulmonary complications that occur after lung and hematopoietic stem cell transplantation.

Amplify on preoperative evaluation and understand the effects of operative procedures and anesthesia on lung function.

Review changes in lung function that occur with aging.

GENERAL CONSIDERATIONS

This chapter presents the clinical aspects of several stresses that can affect lung function. Therapeutic use of numerous drugs has been associated with significant lung dysfunction, and illicit drug use and cigarette smoking exact a tremendous toll on lung health in susceptible individuals. Lung transplantation exposes the donor lung to the remarkable stress of brain death, ischemia-reperfusion, and then recovery in a hostile immune environment. Hematopoietic cell transplantation offers an opportunity for cure of a number of diseases, but this therapy exposes the lung to a variety of noninfectious and infectious injuries. Surgical procedures and general anesthesia cause dysfunction in normal lungs and can represent a critical stress to patients with limited pulmonary reserve. Finally, aging is associated with alterations in pulmonary mechanics and host defense.

DRUG-INDUCED LUNG DISEASE

Note: BOOP, bronchiolitis bliterans with organizing pneumonia.

Clinically, patients present with dyspnea and cough, inspiratory crackles on chest auscultation, and bilateral lower lobe infiltrates on chest x-ray. Mild deterioration of pulmonary function may improve after discontinuing bleomycin. More severe injury, with respiratory insufficiency, can improve after corticosteroid therapy, but mortality rates for this condition are high. Pulmonary function testing with frequent monitoring of diffusion capacity is recommended.

Methotrexate is a folate antagonist that has been used to treat malignant and inflammatory conditions. The incidence of clinical toxicity is less than 10% and occurs more frequently in patients receiving methotrexate for malignancy than in patients treated for inflammatory conditions. Pathologic studies usually demonstrate infiltration of lung parenchyma with mononuclear cells, including lymphocytes and plasma cells. Poorly formed granulomas are also commonly observed. Pulmonary toxicity presents with dyspnea, nonproductive cough, and fever. Chest x-ray often demonstrates bilateral reticular infiltrates, or less commonly, focal infiltrates. Hilar adenopathy and/or pleural effusion are seen in 10%–15%. Diffusion capacity tends to remain intact. Frequently patients also have blood eosinophilia, consistent with a hypersensitivity reaction. Rarely, methotrexate pulmonary toxicity occurs as noncardiogenic pulmonary edema after intrathecal administration or as an acute chest pain syndrome. Discontinuation of methotrexate and treatment with corticosteroids usually leads to clinical improvement. In some cases methotrexate can be rein-stituted following resolution without triggering a subsequent reaction.

Cigarette Smoking

Lung disease is a common complication of substance abuse. A variety of pulmonary pathologic conditions can develop with years of cigarette smoking. Chronic obstructive pulmonary disease (COPD) develops in 10%–20% of heavy smokers. Nonsmokers can develop emphysema due to heritable α₁-antitrypsin deficiency, in which a single amino acid substitution leads to deficiency of this important antiprotease in serum, with aggregation of abnormal protein in liver endoplasmic reticulum. The onset of emphysema varies in susceptible populations: tobacco smokers become symptomatic at about 60–65 years of age, while nonsmokers with α₁-antitrypsin deficiency develop symptomatic disease 10–30 years earlier. Cigarette smokers with α₁-antitrypsin deficiency are highly susceptible to lung injury and emphysema and frequently become symptomatic in the third or fourth decade of life. Treatments include smoking cessation, antiprotease replacement therapy, and lung transplantation.

Respiratory bronchiolitis was previously considered an incidental finding in smoker’s lung, but now appears to be part of a spectrum of disease that includes smoker’s lung, respiratory bronchiolitis, and desquamative interstitial pneumonitis (DIP), in order of increasing severity. Pathologically, alveoli contain numerous brown-pigmented macrophages, and this disease is differentiated from others in the spectrum by extent of involvement (peribronchiolar, not diffuse). All patients with respiratory bronchiolitis smoke heavily, and cough and dyspnea are common. Chest x-rays may be normal or have an interstitial pattern, while high-resolution computed tomography (CT) scans may appear normal or demonstrate a ground-glass pattern. Pulmonary function studies demonstrate mild restriction and a low diffusion capacity. The prognosis is very good, and symptoms usually resolve with smoking cessation.

As with respiratory bronchiolitis, DIP occurs almost exclusively in cigarette smokers. Pathologically, DIP resembles respiratory bronchiolitis, but pigmented macrophages are present diffusely and some fibrosis may be seen in the interstitium. Symptoms develop in the third to fifth decade of life with cough and dyspnea. Chest x-rays often have an interstitial pattern and subpleural ground-glass opacities. One third of the reported cases progress to respiratory failure, while most others improve. Recommended therapies include smoking cessation and corticosteroids.

Smoking is the largest preventable cause of cancer and is responsible for approximately 30% of cancer deaths. Tobacco smoke contains many carcinogens and tumor promoters. It appears to be dose related and young smokers seem to be more susceptible to genetic alterations. Cancers most often associated with smoking include squamous cell of the head and neck and lung cancer. The lung cancers include adenocarcinoma, squamous cell, and small cell carcinoma. Risk decreases in ex-smokers in proportion to the length of time since smoking cessation, but never reaches that of a nonsmoker.

Illicit Drugs

Intravenous injection of oral drugs can also cause pulmonary disease. Two well-described examples are methadone and methylphenidate. Both are associated with panacinar emphysema and severe obstructive lung disease after years of intravenous injection, and methadone injection may cause upper lobe conglomeration and fibrosis that resembles the progressive massive fibrosis of silicosis. Although both methadone and methylphenidate contain talc (magnesium trisilicate) as filler, the damaging ingredient is unknown. Nearly all reported cases of lung disease occurred in cigarette smokers, and many of the patients developed symptoms at a very early age (ie, the third decade of life), suggesting a destructive interaction between cigarette smoke and intravenous drug abuse.

Sir William Osler (1880) first described narcotic-induced pulmonary edema after morphine poisoning. Pulmonary edema following heroin overdose is the modern version of this disease, and most cases resolve within 24–48 hours. The chest x-ray demonstrates bilateral perihilar edema, but unilateral edema has been described. Prolonged respiratory failure suggests complications such as aspiration or pneumonia, or an alternative diagnosis.

Marijuana contains more tar and carbon monoxide per inhalation than tobacco, and also delivers thousands of chemical species to the lung. However, a decline in the pulmonary function of long-term abusers has not been convincingly shown. Recent studies indicate obstructive lung disease risk may be increased in those who smoke both cigarettes and marijuana. Marijuana is often contaminated with Aspergillus, and may cause fungal pneumonia in immunosuppressed patients using the drug for recreational or therapeutic purposes. Marijuana smoking is also associated with bullous lung disease, pneumothorax and pneumomediastinum.

LUNG TRANSPLANTATION

Indications & Contraindications for Transplantation

Common diagnoses for which lung transplantation is being performed include chronic obstructive lung disease, idiopathic pulmonary fibrosis, cystic fibrosis, alpha-1 antitrypsin deficiency and idiopathic pulmonary hypertension. Others include sarcoidosis, lymphangioleiomyomatosis, eosinophilic granuloma, and chronic rejection of a previous lung allograft. The number of lung transplants performed is limited by the availability of transplantable organs. About 10%–15% of patients deemed suitable candidates for lung transplantation die while on the waiting list. Generally, lung transplantation should be considered for patients with nonmalignant advanced lung disease that is unresponsive to medical therapy. In addition, the patient should be free of significant comorbidity. The major contraindications to lung transplantation are poor functional status, significant dysfunction of other major organs, active malignancy within 2 years, extrapulmonary infection, active substance abuse within 6 months (including cigarette smoking), hepatitis C with abnormal liver biopsy and psychosocial instability. Some relative contraindications include osteoporosis, mechanical ventilation and HIV infection.

Ideally, the transplantation should be done at a time when the patient is sufficiently ill to benefit from transplantation but is healthy enough to survive the procedure. Most centers recommend transplantation if the prognosis for survival is less than 2 years on maximal medical therapy. The prospect of improved quality of life is a strong motivation for transplantation, but to maximize the benefit of survival, prognosis and rapidity of clinical deterioration should determine the timing.

COPD is the most common indication for which lung transplantation has been performed. The presence of pulmonary hypertension, hypercarbia, and hypoxemia suggests poor prognosis and should be considered in determining when to proceed with transplantation. Selection guidelines include an FEV₁ less than 25% predicted and/or arterial Pco₂ greater than or equal to 55 mm Hg and/or increased pulmonary artery pressures.