Late-Stage Emphysema: When Medical Therapy Fails

REVIEW

ASOK DAS GUPTA, MD, MRCP JANET MAURER, MD Department of Pulmonary and Critical Care Medicine, Head, Section of Lung Transplantation, Kelsey-Seybold Clinic, Houston, Texas Department of Pulmonary and Critical Care Medicine, Cleveland Clinic

Late-stage emphysema: When medical therapy fails

ABSTRACT OST PATIENTS with chronic obstructive pulmonary disease (COPD) are man- Although most patients with emphysema are managed aged medically, but a small subset of patients medically, a small subset of severely disabled patients may who experience a progressive and accelerated become candidates for surgery. This paper discusses for the decline in lung function, increasing symp- internist who works with emphysema patients the risks, toms, and severe disability1 may be candidates benefits, patient selection criteria, and outcome data for for one of three surgical treatments: three procedures in current use: bullectomy, lung • Bullectomy transplantation, and a new procedure which provides an • Lung transplantation alternative to transplantation—lung volume reduction. • Lung volume reduction. This article will briefly touch on medical management of emphysema, and then review KEY POINTS the rationale, indications, patient selection, All patients with emphysema require maximal maintenance and outcome data for each surgical approach. medical therapy for functional relief and also as a • ELEMENTS OF MAXIMAL MEDICAL THERAPY prerequisite for surgical intervention. Smoking cessation and oxygen therapy are the Patient selection for bullectomy is based on symptoms, cornerstones of management for all patients comorbid states, pulmonary function tests, imaging studies, with severe airflow obstruction and functional and, above all, the size of the bullae. limitation. All patients require maximal maintenance medical therapy—not only for func- Studies fail to show any statistical advantage of double tional relief, but also as a prerequisite for any lung vs single lung transplantation as late as 5 years after surgical intervention. surgery; thus, since donor lungs are scarce, double lung Specific components of medical therapy transplantation should be reserved for select cases. include pharmacotherapy, pulmonary rehabilitation, preventive vaccination, smoking ces- In lung volume reduction, abnormal and nearly functionless sation, and long-term oxygen therapy. When these treatments do not provide enough relief emphysematous lung tissue comprising 20% of the lung is and the patient is able to undergo surgery, con- resected, thus reducing the hyperinflated lungs closer to sideration of bullectomy, lung transplantation, normal lung volume. or lung volume reduction is appropriate.

Drug therapy Pharmacologic interventions aim to relieve symptoms and include short-acting and long- acting beta-2 agonists (albuterol, salmeterol), anticholinergic agents (antimuscarinics), methylxanthines, and steroids.2-3-7 The role of

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TABLE 5 Only smoking cessation and long-term oxygen therapy improve survival Indications for long-term The above interventions are associated with oxygen therapy* symptomatic improvement, but survival benefits have been demonstrated only with smok- Partial pressure of oxygen (Pa02) < 55 mm Hg or oxygen saturation < 88% ing cessation and long-term oxygen therapy. Smoking cessation. Although smoking Pa02 56 to 59 mm Hg or oxygen saturation 89%, if cessation fails to regain lost FEVj, it reduces Electrocardiographic evidence of cor pulmonale, or the accelerated annual rate of decline in FEVi Edema due to congestive heart failure, or seen in smokers, and may even reduce the Hematocrit > 56% decline to levels seen in lifetime nonsmokers Medicare-reimbursable to correct hypoxemia during if stopped at an early stage. Exercise, if Pa02 < 55 mm Hg or oxygen saturation < 88% Oxygen therapy. Both the Medical Sleep, if Pa02 < 55 mm Hg or oxygen saturation < 88% Council Research trial and the Nocturnal Drop in Pa02 > 10 mm Hg or oxygen saturation > 5% with Oxygen Therapy Trial demonstrated a survival signs or symptoms of hypoxia benefit from continuous oxygen therapy, with survival directly related to the total number of 15 16 "Medicare requires recertification and retesting in 60 to 90 days if Pa02 hours of oxygen used. - In patients in whom > 55 mm Hg, or oxygen saturation > 88% when oxygen was prescribed; conventional oxygen delivery systems may be recertification in all patients required after 1 year problematic or fail to achieve adequate oxygenation, a transtracheal oxygen system may be a more effective alternative to achieve steroids in slowing the rate of decline in FEVj therapeutic blood oxygen levels with lower is still unclear; results from ongoing long-term flow rates.17 Physiologic improvement from studies (ISOLDE, EUROSCOP) are expected long-term oxygen therapy includes reduction shortly. Steroids seem to offer clear-cut benefit in dyspnea, maximal voluntary ventilation, when used during acute exacerbations.8 polycythemia, pulmonary hypertension, Smoking Similar benefits during an acute exacerbation hypoxia associated with rapid eye movement cessation and have also been shown with the use of antibi- during sleep, and nocturnal arrhythmias. It otics compared with placebo.9 also results in improved arterial oxygenation, oxygen therapy neuropsychiatric function, and exercise toler- are still the Vaccination ance (table 1). Preventive vaccination against pneumococcus cornerstone of and annual vaccination against influenza are • BULLECTOMY management advised. A bulla is an airspace greater than 1 cm in Pulmonary rehabilitation diameter formed as a result of pulmonary tis- All patients with emphysema should under- sue destruction.18 It maintains direct commu- take a pulmonary rehabilitation program and nication with bronchioles, but its walls lack should continue a home-based exercise pro- vascularity. Thus, the bulla does not partici- gram for life.10-12 An 8-week comprehensive pate in gas exchange and acts more like a rehabilitation program has been shown to space-occupying lesion with compressive result in a greater increase in maximal exercise effects on surrounding parenchyma. tolerance, oxygen uptake, and exercise endurance, with improvement in perceived Patient selection for bullectomy breathlessness and muscle fatigue when com- Patient selection for bullectomy should be pared to a similar period of education alone.13 based on symptoms, comorbid states, pul- Similar improvement in exercise tolerance monary function tests, imaging studies, and, and quality of life (for parameters of dyspnea, above all, the size of the bullae. Bullae in fatigue, emotion, and mastery) has been patients with emphysema are generally from 1 observed with home rehabilitation compared cm to 4 cm in diameter, but are sometimes to controls.14 much larger, occupying more than one third of

416 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 66 • NUMBER 7 JULY / AUGUST 1999 Downloaded from www.ccjm.org on September 27, 2021. For personal use only. All other uses require permission. the hemithorax.19 The larger the bulla, the TABLE 2 stronger the indication for surgery. Bullae predispose patients to pneumo- Selection criteria thorax. In one series of patients with bullous for lung transplantation 20 emphysema, the incidence of pneumotho- Between 70% and 130% of ideal body weight rax was 15.7% among patients followed with- Taking only a minimal dose of steroids (< 20 mg of prednisone) out surgery. In the same series, pneumothorax Approximate maximum age (years): was the indication for bullectomy in 19% of 65 (single lung recipients) cases. 60 (double lung recipients) Asymptomatic patients, irrespective of 55 (heart-lung recipients) the size of the bulla, generally are not operat- No substance abuse for more than 6 months ed on unless they work at a job that puts them Creatinine clearance > 50 mg/mL/min at high risk for pneumothorax (eg, commer- Chronic obstructive pulmonary disease 21 cial airline pilots). FEV| < 25% of predicted (without reversibility) Significant dyspnea remains the most Hypercapnia (PaC02 > 55 mm Hg) common indication for bullectomy. Pulmonary hypertension The bullae should be the likely cause of Progressive disease (eg, cor pulmonale) symptoms. If dyspnea and reduced pulmonary function are caused by widespread emphysema rather than by a giant bulla, then bullectomy may have no effect on symptoms or lung func- decrease in total lung volume may improve tion. For example, if a bulla is not a giant bulla diaphragmatic contour. Reduction in physio- (ie, it occupies less than 30% of the hemitho- logic dead space is unlikely, as bullae normal- rax) but the patient has a severely reduced ly do not participate in gas exchange. FEVi, a reduced diffusing capacity, hypoxia, Long-term results in properly selected hypercarbia, and disabling dyspnea, then patients have been good. The best outcome symptoms are likely due to the underlying has been seen in patients with giant bullae emphysema rather than to the bulla. occupying more than 50% of the hemitho- Bullectomy is 25 On the other hand, in a symptomatic rax and near-normal underlying lung func- generally for patient with a giant bulla and normal sur- tions. Subjective improvement in symptoms is rounding lung tissue, significant improvement often greater than objective increases in lung bullae that 26 27 can be expected. Younger patients with no function. - Despite return of symptoms in occupy at least comorbid conditions, an FEVj > 40% of pre- some patients because of continued smok- dicted,22 normal diffusing capacity,22-24 and ing,24 functional improvements in the major- 30% of the 22 24 normal blood gases - are good candidates ity have been sustained over 5 to 10 years, and hemithorax for bullectomy and show a reduction in dysp- even as long as 24 years.20-28-29 nea, improved exercise tolerance, increased FEVj, and sustained benefits over years. • LUNG TRANSPLANTATION

Evaluation for bullectomy Lung transplantation is the ultimate option Chest computed tomography (CT) is current- for patients with severe end-stage lung dis- ly the preferred method of evaluation in these ease, and emphysema remains the most com- patients. It easily demonstrates the size of the mon indication for transplantation. bulla, the status of surrounding pulmonary vasculature, and underlying lung disease. Patient selection A number of general-health criteria and dis- Bullectomy outcomes ease-specific characteristics need to be ful- Physiological improvement following bullec- filled before patients are considered good can- tomy is manifested by decreased airway and didates (TABLE 2). In general, prerequisites for pulmonary vascular resistance, reduced func- successful lung transplantation include: tional residual capacity, and increased elastic • Severe disease with significantly recoil of the lung. Furthermore, the resulting impaired activities of daily living

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• Motivated patient with no associated TABLE 3 comorbid conditions Absolute and relative contraindications • Completion of maximal medical therapy and optimal pulmonary rehabilitation. to lung transplantation The goal of lung transplantation is Absolute improved quality of life rather than prolonged Hepatitis B surface antigen positivity, hepatitis C with liver disease survival. Acutely ill, unstable patients on Malignancy within 2 years, except skin cancer mechanical ventilation are not candidates. Significant untreatable coronary artery disease or left ventricular However, stable patients on noninvasive ven- dysfunction, except for heart-lung recipients tilation may be evaluated for transplantation. Progressive neuromuscular disease Hypercapnia and significant pulmonary HIV infection hypertension are acceptable in lung transplantation candidates, whereas this is not true for Creatinine clearance < 50 mg/mL/min candidates for lung volume reduction. Relative Colonization with fungal or atypical mycobacterial infections Contraindications Symptomatic osteoporosis Hepatitis B surface antigen positivity, hepati- Systemic disease with end-organ damage tis C with histologic evidence of liver disease, Kyphoscoliosis human immunodeficiency virus infection, Sputum with panresistant organisms and progressive neuromuscular disease are Unresolved psychosocial issues among the absolute contraindications to Mechanical ventilation (invasive) transplantation (TABLE 3). For patients treated Noncompliance to medical therapy for cancer, a 2 -year disease-free interval is recommended before transplantation, except for basal and squamous cell skin carcinoma, in which case there is no such requirement. treatment plans should be addressed. However, in the case of breast cancer (stage 2 Attempts should be made to eradicate col- or higher), extracapsular renal cell tumor, onization with fungal and atypical mycobacte- Emphysema colon carcinoma (> Duke A), and melanoma rial species. However, adequately treated is the most (level III or deeper), most lung transplanta- mycobacterial disease is not a contraindication centers opt for a 5-year disease-free inter- tion to lung transplantation. common val before considering transplantation. indication for Relative contraindications. Symptomatic Single lung transplantation: osteoporosis is a relative contraindication to Preferred method despite drawbacks lung transplant lung transplantation. Patients with marked Single lung transplantation is the preferred kyphosis or significant back pain may be method of transplantation now offered to denied transplantation. Patients with less than emphysema patients. Most clinicians report normal bone densitometry T scores in the hip good early and intermediate results,30 and it or spine are placed on therapy, usually oral bis- allows for a larger number of recipients than phosphonates. Asymptomatic patients with T double lung transplant. scores of less than -2.5 standard deviations Hyperinflation of the native lung is an from the mean are considered at high risk and important complication of single lung trans- receive preoperative intravenous bisphospho- plantation. It may occur if the donor lung is nate therapy. All attempts should be made to small, if there is significant bullous disease pre- discontinue use of corticosteroids. sent in the native lung, or if there is early allo- Patients need to weigh between 70% and graft rejection or other pulmonary complica- 130% of their ideal body weight. Periodic bio- tion. Although this problem is reported by chemical monitoring is recommended to satis- many physicians, overall impact on patient fy compliance with freedom from substance outcome appears small. In the rare cases of sig- abuse. Psychosocial issues that may negatively nificant graft compression, several corrective impact patient outcome should be resolved, options (eg, pneumonectomy, lobectomy, bul- and noncompliance with medical care or lectomy, lung volume reduction) are available.

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Infection of the native lung is another Transplantation outcomes problem, with the potential of contamination After transplantation, most patients exhibit of the transplanted lung, threatening its func- an improvement in dyspnea from New York tion. Of particular concern is Aspergillus colo- Heart Association class 3 or 4 to class 1. Single nization of the native lung which may act as a lung transplantation patients may achieve an reservoir for persistent infection.31 FEVi measurement of more than 50%33 and a marked improvement in both graded and Double lung transplantation: nongraded exercise capacity.34 Maximum oxy- reserve for select patients gen uptake ranges from 45% to 60%, similar Although early functional outcomes are bet- to that for double lung transplant recipients,35 ter with double lung transplantation and the with a marked increase in 6-minute walking potential for certain complications is much distances by 3 months after transplantation.36 less than with single lung transplantation, survival data have failed to show any statistically • LUNG VOLUME REDUCTION significant advantage of double lung over single lung transplantation up to 5 years after The number of emphysema patients with end- surgery. Thus, in view of the great shortage of stage lung disease presenting to transplanta- donor lungs, double lung transplantation tion centers far exceeds the number of donor should he reserved either for very young organs available, so alternatives to transplan- patients or for those in whom there is a com- tation are necessary. Lung volume reduction is pelling reason to remove both lungs, such as an effective alternative gaining popularity. concomitant bronchiectasis or giant bullous Lung volume reduction seeks to correct a disease. variety of physiologic variables in the emphysematous lung, specifically elastic lung recoil Lung transplantation mortality pressure and expiratory flow. Abnormal and and complications nearly functionless emphysematous lung tis- Perioperative mortality for lung transplanta- sue comprising 20% of the lung is resected, The number tion has decreased significantly during the thus reducing the hyperinflated lungs closer to past decade, and both single lung and double normal lung volume. of patients lung methods in emphysema patients have In emphysematous lungs, lung volumes with end-stage less than a 10% operative mortality.32 Causes are increased, the elastic properties are lost, of early mortality (< 90 days) include infec- and circumferential pull on the bronchioles is disease far tion (35%), early graft failure due to reperfu- impaired, especially during expiration, leading exceeds the sion injury (15%), cardiac dysfunction, to a greater degree of obstruction. After lung rejection, bleeding, and anastomotic break- volume reduction surgery, the increased lung donor organ down.32 volumes are reduced, and the physiologic cir- supply Late mortality is primarily related to cumferential pull is partially restored. infection, chronic rejection, or bronchioli- Reduction in lung volumes also allows the tis obliterans. Aggressive infection prophy- diaphragm to attain a more dome-shaped con- laxis can restrict infectious complications tour that permits it to function more effec- in the immediate perioperative period, but tively, and the thoracic cage to assume a more opportunistic infections related to im- normal shape. munosuppressive agents are a constant This procedure was developed between danger. 1957 and 1961, but a high complication rate Complications of drug-induced immuno- and an unacceptable mortality rate led to its suppression in the posttransplantation period abandonment until its revision and resur- include lymphoreticular and non-lym- gence in the early 1990s.37 phoreticular malignancies, hypertension, renal toxicity (from cyclosporine and Patient selection tacrolimus), gastrointestinal problems, The general medical patient selection criteria cyclosporine-induced neurotoxicity, osteo- are less stringent for lung volume reduction porosis, and hyperlipidemia. than for lung transplantation, but the disease-

CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 66 • NUMBER 7 JULY / AUGUST 1999 422 Downloaded from www.ccjm.org on September 27, 2021. For personal use only. All other uses require permission. TABLE 2 Eligibility factors for lung transplantation and lung volume reduction

FACTORS LUNG LUNG TRANSPLANTATION VOLUME REDUCTION

Age > 65 years Not allowed Allowed Coexistent pulmonary infection or bronchiectasis Not allowed Allowed Homogeneous disease distribution Allowed Possibly allowed Previous thoracotomy Allowed Not allowed Social support system Important Less important Financial issues Important Less important

FEVt < 20% of predicted Usually required Not required Total lung capacity No minimum > 100% required

Pa02 (on room air) No minimum > 45% required

PaC02 No maximum < 60 mm Hg required Pulmonary arterial pressure (mean) No maximum < 35 mm Hg required

specific criteria are more restrictive (TABLE 4). ual preferences should be clarified. For For example, there is no age restriction, some younger patients, lung volume reduction comorbid disease states are allowed, and a may provide enough improvement to post- solid psychosocial support system is not con- pone the need for transplantation. sidered as crucial. Although patients have sig- Furthermore, in either group of patients, nificant functional disabilities, the ability to lung volume reduction may be a bridge to Air leaks are complete a pulmonary rehabilitative program transplantation while patients await a donor and some exercise tolerance (such as the abil- organ. For a patient whose FEV[ is severely the most ity to walk at least 140 meters) are essential reduced (< 15%), pulmonary damage may be common prerequisites for lung volume reduction so severe that lung transplantation is the complication surgery (TABLES). only option. after lung Choosing between lung volume reduction Complications and transplantation Persistent air leaks are the most common com- volume Despite the differences in specific criteria for plication following lung volume reduction. reduction king volume reduction vs lung transplanta- Other complications include pneumonia, tion, a small group of patients qualifies for reintubation, need for tracheostomy, wound either procedure, and the choice of treatment infection, arrhythmias, phrenic nerve palsies, must be individualized. gastrointestinal problems including bowel per- For older groups of patients closer to the foration, development of postoperative pul- transplantation age restriction (see TABLE 2), monary hypertension, thrombophlebitis, the benefits of lung volume reduction should myocardial infarction (in older patients), and be weighed against those obtained from lung significant anxiety and panic attacks. Anxiety transplantation. and panic attacks have been associated with For example, lung function is improved an increase in morbidity. much more with transplantation than with Careful attention to preoperative exacer- lung volume reduction, although at 1 year bation, early management of anxiety and the exercise tolerance is the same.38 Thus, panic attacks, avoidance of narcotic anal- although some would offer lung transplanta- gesics beyond the first couple of days to tion, the choice is controversial and individ- reduce bowel problems, extubation within

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TABLE 5 improvement in lung function seen after lung volume reduction will persist. Maximal Criteria for lung volume improvement in lung function indices are reduction surgery seen at 6 months after surgery, and although No age restriction improvements are maintained at 1 year, there Marked disability after completing pulmonary rehabilitation may be a trend towards falling indices com- (see text) pared with the 6-month values.40,41 Long- No tobacco use for at least 4 months term improvement in measurements of other functional aspects such as dyspnea, which may Imaging must show heterogeneous disease (homogeneous disease has more stringent criteria) or may not be related to commonly measured pulmonary function, has not been carefully Pulmonary function tests (all after bronchodilator adminis- tration; lung volumes measured by plethysmography) studied. Forced expiratory volume in 1 second (FEV,) < 45%; if age > 70 years, an FEV-, > 15% predicted) Lung volume reduction: major questions Lung volume reduction is a palliative proce- Total lung capacity > 110% dure that does not halt, but only slows, the Residual volume > 150% rate of functional decline for emphysema Diffusing capacity of the lung for carbon monoxide < 70% patients. The disease will progress, and symp- Absence of bronchodilator response (FEV, change < 30% toms will likely worsen. Still, data suggest that and 300 mL) significant short-term improvement and par-

PaC02 < 60 mm Hg tial reversal of the physiologic derangements

Pa02 > 45 mm Hg on room air can be obtained. Mean pulmonary artery pressure < 35 mm Hg or peak Major questions remain about the role of systolic pressure < 45 mm Hg lung volume reduction: • Who are the best candidates for the procedure, and does the procedure have an acceptably good effect? the operating or recovery room, and reinsti- • If there is a benefit, how long does it tution of postoperative pulmonary rehabili- last, and does it justify both the risk to poten- tation as soon as possible could help obviate tial transplantation candidates and the cost in some complications and permit an earlier money and resources? hospital discharge. The role of lung volume reduction vs Perioperative mortality is reported maximal medical therapy and pulmonary between 0% and 18%, with most centers rehabilitation need to be more carefully under 10%.«39 assessed in patients with advanced COPD. Can medical therapy and rehabilitation alone Lung volume reduction outcomes result in improvements similar to those Successful lung volume reduction results in a reported for lung volume reduction? variable improvement in elastic lung To answer some of these tethering issues, recoil.38 Cumulative evidence suggests an a multicenter study is underway. This study, increase in FEVj of 13% to 96% in a diverse the National Emphysema Treatment Trial, is a population of patients utilizing different sur- 17-center prospective trial involving 4,700 gical techniques and variable follow-up.19 patients randomized either to medical therapy Upper lobe predominance and elevated base- and rehabilitation or to surgery. Patients will line plethysmographic residual volume are be followed for 5 years. • associated with a good outcome. There may be a disproportionate subjective improve- • REFERENCES ment in symptoms (eg, quality of life) com- 1. Kanner RE. Early intervention in chronic obstructive pul- pared with objective findings in lung func- monary disease: A review of the lung health study tion studies. results. Med Clin North Am 1996; 80:523-547. 2. Celli BR. Current thoughts regarding treatment of chron- Long-term follow-up data are still not ic obstructive pulmonary disease. Med Clin North Am available, and it is not clear how long the 1996; 80:589-609.

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Clin Chest term results of surgery for bullous emphysema. J Med 1997; 18:259-276. Thorac Cardiovasc Surg 1974; 68:566-568. 21. Mehran RJ, Deslauriers J. Indications for surgery and ADDRESS: Janet R. Maurer, MD, Pulmonary and Critical Care patient workup for bullectomy. Chest Surg Clin N Medicine, A90, The Cleveland Clinic Foundation, 9500 Euclid North Am 1995; 5:717-734. Avenue, Cleveland, OH 44195, e-mail [email protected].

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