THE WESTERN JOURNAL OF MEDICINE
AUGUST 1992
2
171
vein studies remain negative in this cohort, treatment can be safely withheld. These investigators do emphasize the need for serial leg vein studies and also call for confirmation of
within the thrombus (as long as 6 hours). Combining the duration of pharmacologic effects with the observation that an increased diffusion of thrombolytic agents into thrombus takes place when high circulating drug levels are present has led to the development of bolus-dosing protocols for treating pulmonary emboli with thrombolytic agents. Studies of animals and initial clinical trials with both urokinase and tissue plasminogen activator suggest that this approach may be more efficacious, with possibly less risk of sustained bleeding than the standard continuous infusion regimens. Many investigators think that thrombolytic therapy should be used to treat any pulmonary embolus causing hemodynamic instability or respiratory compromise. More recently, some have proposed using echocardiography to evaluate large pulmonary emboli in stable patients; any evidence of right ventricular dysfunction or dilation is used as a rationale for treating with thrombolytic agents. This approach is currently being evaluated in a randomized trial. A decade ago it was reported that the diffusing capacity of the lungs for carbon monoxide in patients treated with thrombolytic therapy was better preserved than in those treated with heparin. The explanation was that the pulmonary capillary blood volume (pulmonary microcirculation) is better preserved after thrombolytic therapy than after standard heparin anticoagulation. A preliminary report of follow-up hemodynamic examinations of these patients found that those treated with thrombolytic agents had lower mean pulmonary arterial pressures and pulmonary vascular resistance at rest and during exercise than did those who had been treated with heparin. The significance of the modest hemodynamic differences is unclear, however, and the question of whether the routine use of thrombolytic therapy for less substantial pulmonary emboli is appropriate to preserve the pulmonary microcirculation remains unanswered.
o
THI
their
findings.
e
157
o
ANTHONY M. COSENTINO, MD
San Francisco, California REFERENCES Agnelli G, Cosmi B, Ranucci V, et al: Impedance plethysmography in the diagnosis of asymptomatic deep vein thrombosis in hip surgery. Arch Intern Med 1991; 151:2167-2171 Hull RD, Raskob GE, Coates G, Panju AA, Gill GJ: A new noninvasive management strategy for patients with suspected pulmonary embolism. Arch Intern Med 1989; 149:2549-2555 Pedersen OM, Aslaksen A, Vik-Mo H, Bassoe AM: Compression ultrasonography in hospitalized patients with suspected deep venous thrombosis. Arch Intern Med 1991; 151:2217-2220 The PIOPED Investigators: Value of the ventilation/perfusion scan in acute pulmonary embolism. JAMA 1990; 263:2753-2759
Thrombolytic Treatment of Pulmonary Embolism OVER THE PAST SEVERAL YEARS, there has been renewed interest in the use of thrombolytic therapy for treating venous thromboembolic disease. This is a consequence of both the availability of new thrombolytic agents and the interest in clot dissolution prompted by advances in treating coronary
thrombolysis. At present, the Food and Drug Administration has approved three thrombolytic agents for the treatment of pulmonary embolism: streptokinase, urokinase, and recombinant tissue plasminogen activator (rt-PA). Only streptokinase has been approved for treating deep venous thrombosis. All of these agents lower fibrinogen, plasminogen, and ao2-antiplasmin levels and generate a systemic lytic state. Fibrin selectivity has not yet proved to be of clinical importance nor has it been associated with lower rates of bleeding complications. Cost does differentiate among the several available thrombolytic agents. Although total costs vary with the duration of therapy, the total amount of the thrombolytic agent administered, the varied requirements for monitoring and blood work that different patients and protocols necessitate, and the occurrence and cost of complications, streptokinase is the least expensive of the available agents. According to the standard protocols for treating venous thromboembolism, streptokinase and urokinase are administered by continuous intravenous infusion for periods of 12 to 72 hours, whereas tissue plasminogen activator is given as a 100-mg dose over 2 hours. Despite these recommendations, it is clear the optimal dosing regimens and duration of thrombolytic treatment have not yet been established. For continuous infusion therapy, setting the duration of therapy by the clock makes little sense; once thrombolytic treatment is initiated, it should be continued until either all clot amenable to thrombolysis has been dissolved or a complication of the therapy has been identified. One possible approach is to monitor the level of fibrin-degradation products (fibrin-split products), continuing thrombolytic treatment until levels are normal, indicating the cessation of notable clot lysis. For rtPA, it is not clear if the short duration of therapy-based on the coronary thrombolysis model-is always sufficient to lyse the relatively large clot volume found in substantial pulmonary emboli and proximal deep venous thrombosis. Current studies of the regimens for thrombolytic treatment of pulmonary emboli take into account the differences between the circulating half-lives of the thrombolytic agents (less than 25 minutes) and the duration of fibrinolytic activity
HAROLD I. PALEVSKY, MD THOMAS A. RAFFIN, MD Stanford, California
REFERENCES Agnelli G, Parise P: Bolus thrombolysis in venous thromboembolism. Chest 1992; 101: 172S-182S Come PC: Echocardiographic evaluation of pulmonary embolism and its response to therapeutic interventions. Chest 1992; 101: 151 S- 162S Goldhaber SZ: Thrombolysis in venous thromboembolism: An international perspective. Chest 1990; 97:176S- 1 81 S Palevsky HI, Fishman AP: Diagnosis and treatment of pulmonary embolism and deep venous thrombosis, In Fishman AP (Ed): Update: Pulmonary Disease and Disorders. New York, NY, McGraw-Hill, 1992, pp 451464
Lung-Assist Devices Two KINDS OF DEVICES are used to assume the gas-exchange task of the lung. The first is an artificial lung, which is needed in part because of the lack of a suitable supply of healthy lungs for transplantation. The second is a lung-assist device to bridge the gap until lung transplantation can be accomplished. It is also used in patients with a severe abnormality in the gas-exchange process, as in the adult respiratory distress syndrome. Lung-assist devices may also help reduce intrathoracic pressure when patients are on mechanical ventilation, possibly resulting in decreased morbidity and mortality associated with the adult respiratory distress syndrome. The two approaches to lung-assist devices currently being evaluated are extracorporeal carbon dioxide removal and intravascular oxygenator. on
In 1974 the National Institutes of Health funded a study the efficacy of extracorporeal membrane oxygenation in
EPITOMES-CHEST DISEASES
172
the adult respiratory distress syndrome. The control group was treated with mechanical ventilation and positive endexpiratory pressure. The result in both groups was about 10% survival, leading to the conclusion that extracorporeal membrane oxygenation has no role in this disorder. In the early 1980s, neonatologists had better success in the treatment of neonatal respiratory distress syndrome, with an overall survival rate reaching 78%. Several recent European reports have suggested that the survival rate for patients treated with extracorporeal membrane oxygenation who met the entry criteria of the original 1974 study was close to 50%, reviving interest in lung-assist devices. There have been several important improvements in the technology, such as thromboresistant coating of the surfaces used, improved efficiency of membranes, and better pumps to reduce hemolysis and platelet destruction. The major change was that extracorporeal membrane oxygenation was modified into extracorporeal CO2 removal. In the former procedure, blood completely bypasses the heart and the lungs. This technique is designed to support the failing lungs and heart. In extracorporeal CO2 removal, blood is drained from and returned to the vena cava after membrane gas exchange, therefore only supporting the lungs. Extracorporeal CO2 removal also allows the use of low-frequency mechanical ventilation, low positive end-expiratory pressure, and continuous low-flow oxygen, but oxygen uptake continues to occur mainly in the lungs. The technique is labor intensive, requires capital equipment, and runs at high cost. The intravascular oxygenator is an intracorporeal gasexchange device placed in the vena cava. It is constructed with polypropylene hollow fibers coated with ultrathin biocompatible siloxane. All blood-contacting surfaces are also coated with covalently bonded heparin. Oxygen is sucked through the fibers, gas exchange occurs through the membranes, and blood is oxygenated intravenously. Placement and maintenance are relatively simple and inexpensive. Because of its relatively small surface area, its capacity is only a third to half of the gas exchange necessary to maintain aerobic metabolism. Thus, extracorporeal membrane oxygenation is an acceptable technique in the management of neonates with respiratory distress syndrome. In adults, all three techniques are still experimental but have promise. The development of a totally artificial lung remains some time away. DAVID M. GELMONT, MD South Pasadena, California
REFERENCES Anderson HL III, Delius RE, Sinard JM, et al: Early experience with the adult extracorporeal membrane oxygenation in the modem era. Ann Thorac Surg 1992; 53:553-563 Lally KP, Clark R, Schebdeman C, et al: Extracorporeal membrane oxygenation in the newbom. Milit Med 1990; 155:377-379
Bronchiolitis Obliterans Organizing Pneumonia THE TERM bronchiolitis obliterans organizing pneumonia (BOOP) was coined in 1985 to describe a lung disease characterized histologically by the presence of intraluminal fibroblastic proliferation. In Europe, BOOP is also known as cryptogenic organizing pneumonitis. It has recently been suggested that the disorder be renamed as cryptogenic intramural fibrosis of distal air spaces. Bronchiolitis obliterans organizing pneumonia is divided into primary or idiopathic and secondary. The secondary BOOP may occur in association with certain infections-
with Legionella, Mycoplasma, or Adenovirus species-the inhalation oftoxic gases (nitrogen dioxide), graft-versus-host disease in bone marrow and heart-lung transplant recipients, and collagen vascular diseases. It is, however, the idiopathic or primary BOOP that enters in the differential diagnosis of diffuse interstitial lung disease. Because of certain common clinical and physiologic abnormalities, BOOP is often misdiagnosed as idiopathic pulmonary fibrosis, sarcoidosis, pneumoconiosis, hypersensitivity pneumonitis, or chronic eosinophilic pneumonia. It is important that BOOP, because of its benign course and favorable response to corticosteroids, is not overlooked or misdiagnosed. Idiopathic BOOP occurs mainly in adults, with a peak incidence in the sixth decade; women and men are affected equally. Most patients have a subacute illness with cough, dyspnea, fever, and fatigue of a few weeks' duration. The patient's sedimentation rate is often elevated. Although auscultation may reveal rales, in a third of patients the results of a pulmonary examination are normal. Hypoxemia occurs in almost all patients. Lung volumes are reduced, but airway obstruction is not a feature. Diffusing capacity is impaired. Chest roentgenograms show bilateral patchy airspace densities, commonly in peripheral areas, and many other radiographic patterns have also been reported. Honeycombing is rare. The conventional and high-resolution computed tomographic scan findings are nonspecific, but these new techniques are helpful in distinguishing BOOP from idiopathic pulmonary fibrosis and granulomatous lung disease. On histologic examination, the lungs display immature-appearing plugs in the respiratory bronchioles, alveolar ducts, and peribronchial alveolar spaces. The alveolar spaces also contain foamy cells reflecting the proximal airway obstruction. Alveolar septa are thickened and contain mononuclear cell infiltrate. The presence of intraluminal plugs of fibroblasts, however, distinguishes BOOP not only from idiopathic pulmonary fibrosis but also from other interstitial lung disorders. When should a clinician think about a diagnosis of bronchiolitis obliterans organizing pneumonia? Internists and pulmonologists should consider including BOOP in the differential diagnosis of a subacute interstitial pneumonia, particularly when the patient has influenza-like features with cough, dyspnea, fever, malaise, and weight loss. A poor or unsatisfactory response to antibiotics is another feature favoring this diagnosis. A good transbronchial lung biopsy specimen in conjunction with a strongly suggestive clinical history and examination is in many cases adequate to establish the diagnosis. An open-lung biopsy is needed when a transbronchial biopsy fails to establish the diagnosis. This pneumonia has an excellent prognosis. It responds well to corticosteroids; almost two thirds ofthe patients in one study improved with the use of corticosteroids. Fewer than 5% of patients die of respiratory failure. Idiopathic bronchiolitis obliterans organizing pneumonia was recently added to the long list of interstitial disorders. The disease has a benign course with an excellent response to corticosteroids, but we remain ignorant of its cause. OM P. SHARMA, MD Los Angeles, California
REFERENCES Bellomo R, Finlay M, McLaughlin P, Tai E: Clinical spectrum of cryptogenic organizing pneumonitis. Thorax 1991; 46:554-558
AUGUST 1992
2
171
vein studies remain negative in this cohort, treatment can be safely withheld. These investigators do emphasize the need for serial leg vein studies and also call for confirmation of
within the thrombus (as long as 6 hours). Combining the duration of pharmacologic effects with the observation that an increased diffusion of thrombolytic agents into thrombus takes place when high circulating drug levels are present has led to the development of bolus-dosing protocols for treating pulmonary emboli with thrombolytic agents. Studies of animals and initial clinical trials with both urokinase and tissue plasminogen activator suggest that this approach may be more efficacious, with possibly less risk of sustained bleeding than the standard continuous infusion regimens. Many investigators think that thrombolytic therapy should be used to treat any pulmonary embolus causing hemodynamic instability or respiratory compromise. More recently, some have proposed using echocardiography to evaluate large pulmonary emboli in stable patients; any evidence of right ventricular dysfunction or dilation is used as a rationale for treating with thrombolytic agents. This approach is currently being evaluated in a randomized trial. A decade ago it was reported that the diffusing capacity of the lungs for carbon monoxide in patients treated with thrombolytic therapy was better preserved than in those treated with heparin. The explanation was that the pulmonary capillary blood volume (pulmonary microcirculation) is better preserved after thrombolytic therapy than after standard heparin anticoagulation. A preliminary report of follow-up hemodynamic examinations of these patients found that those treated with thrombolytic agents had lower mean pulmonary arterial pressures and pulmonary vascular resistance at rest and during exercise than did those who had been treated with heparin. The significance of the modest hemodynamic differences is unclear, however, and the question of whether the routine use of thrombolytic therapy for less substantial pulmonary emboli is appropriate to preserve the pulmonary microcirculation remains unanswered.
o
THI
their
findings.
e
157
o
ANTHONY M. COSENTINO, MD
San Francisco, California REFERENCES Agnelli G, Cosmi B, Ranucci V, et al: Impedance plethysmography in the diagnosis of asymptomatic deep vein thrombosis in hip surgery. Arch Intern Med 1991; 151:2167-2171 Hull RD, Raskob GE, Coates G, Panju AA, Gill GJ: A new noninvasive management strategy for patients with suspected pulmonary embolism. Arch Intern Med 1989; 149:2549-2555 Pedersen OM, Aslaksen A, Vik-Mo H, Bassoe AM: Compression ultrasonography in hospitalized patients with suspected deep venous thrombosis. Arch Intern Med 1991; 151:2217-2220 The PIOPED Investigators: Value of the ventilation/perfusion scan in acute pulmonary embolism. JAMA 1990; 263:2753-2759
Thrombolytic Treatment of Pulmonary Embolism OVER THE PAST SEVERAL YEARS, there has been renewed interest in the use of thrombolytic therapy for treating venous thromboembolic disease. This is a consequence of both the availability of new thrombolytic agents and the interest in clot dissolution prompted by advances in treating coronary
thrombolysis. At present, the Food and Drug Administration has approved three thrombolytic agents for the treatment of pulmonary embolism: streptokinase, urokinase, and recombinant tissue plasminogen activator (rt-PA). Only streptokinase has been approved for treating deep venous thrombosis. All of these agents lower fibrinogen, plasminogen, and ao2-antiplasmin levels and generate a systemic lytic state. Fibrin selectivity has not yet proved to be of clinical importance nor has it been associated with lower rates of bleeding complications. Cost does differentiate among the several available thrombolytic agents. Although total costs vary with the duration of therapy, the total amount of the thrombolytic agent administered, the varied requirements for monitoring and blood work that different patients and protocols necessitate, and the occurrence and cost of complications, streptokinase is the least expensive of the available agents. According to the standard protocols for treating venous thromboembolism, streptokinase and urokinase are administered by continuous intravenous infusion for periods of 12 to 72 hours, whereas tissue plasminogen activator is given as a 100-mg dose over 2 hours. Despite these recommendations, it is clear the optimal dosing regimens and duration of thrombolytic treatment have not yet been established. For continuous infusion therapy, setting the duration of therapy by the clock makes little sense; once thrombolytic treatment is initiated, it should be continued until either all clot amenable to thrombolysis has been dissolved or a complication of the therapy has been identified. One possible approach is to monitor the level of fibrin-degradation products (fibrin-split products), continuing thrombolytic treatment until levels are normal, indicating the cessation of notable clot lysis. For rtPA, it is not clear if the short duration of therapy-based on the coronary thrombolysis model-is always sufficient to lyse the relatively large clot volume found in substantial pulmonary emboli and proximal deep venous thrombosis. Current studies of the regimens for thrombolytic treatment of pulmonary emboli take into account the differences between the circulating half-lives of the thrombolytic agents (less than 25 minutes) and the duration of fibrinolytic activity
HAROLD I. PALEVSKY, MD THOMAS A. RAFFIN, MD Stanford, California
REFERENCES Agnelli G, Parise P: Bolus thrombolysis in venous thromboembolism. Chest 1992; 101: 172S-182S Come PC: Echocardiographic evaluation of pulmonary embolism and its response to therapeutic interventions. Chest 1992; 101: 151 S- 162S Goldhaber SZ: Thrombolysis in venous thromboembolism: An international perspective. Chest 1990; 97:176S- 1 81 S Palevsky HI, Fishman AP: Diagnosis and treatment of pulmonary embolism and deep venous thrombosis, In Fishman AP (Ed): Update: Pulmonary Disease and Disorders. New York, NY, McGraw-Hill, 1992, pp 451464
Lung-Assist Devices Two KINDS OF DEVICES are used to assume the gas-exchange task of the lung. The first is an artificial lung, which is needed in part because of the lack of a suitable supply of healthy lungs for transplantation. The second is a lung-assist device to bridge the gap until lung transplantation can be accomplished. It is also used in patients with a severe abnormality in the gas-exchange process, as in the adult respiratory distress syndrome. Lung-assist devices may also help reduce intrathoracic pressure when patients are on mechanical ventilation, possibly resulting in decreased morbidity and mortality associated with the adult respiratory distress syndrome. The two approaches to lung-assist devices currently being evaluated are extracorporeal carbon dioxide removal and intravascular oxygenator. on
In 1974 the National Institutes of Health funded a study the efficacy of extracorporeal membrane oxygenation in
EPITOMES-CHEST DISEASES
172
the adult respiratory distress syndrome. The control group was treated with mechanical ventilation and positive endexpiratory pressure. The result in both groups was about 10% survival, leading to the conclusion that extracorporeal membrane oxygenation has no role in this disorder. In the early 1980s, neonatologists had better success in the treatment of neonatal respiratory distress syndrome, with an overall survival rate reaching 78%. Several recent European reports have suggested that the survival rate for patients treated with extracorporeal membrane oxygenation who met the entry criteria of the original 1974 study was close to 50%, reviving interest in lung-assist devices. There have been several important improvements in the technology, such as thromboresistant coating of the surfaces used, improved efficiency of membranes, and better pumps to reduce hemolysis and platelet destruction. The major change was that extracorporeal membrane oxygenation was modified into extracorporeal CO2 removal. In the former procedure, blood completely bypasses the heart and the lungs. This technique is designed to support the failing lungs and heart. In extracorporeal CO2 removal, blood is drained from and returned to the vena cava after membrane gas exchange, therefore only supporting the lungs. Extracorporeal CO2 removal also allows the use of low-frequency mechanical ventilation, low positive end-expiratory pressure, and continuous low-flow oxygen, but oxygen uptake continues to occur mainly in the lungs. The technique is labor intensive, requires capital equipment, and runs at high cost. The intravascular oxygenator is an intracorporeal gasexchange device placed in the vena cava. It is constructed with polypropylene hollow fibers coated with ultrathin biocompatible siloxane. All blood-contacting surfaces are also coated with covalently bonded heparin. Oxygen is sucked through the fibers, gas exchange occurs through the membranes, and blood is oxygenated intravenously. Placement and maintenance are relatively simple and inexpensive. Because of its relatively small surface area, its capacity is only a third to half of the gas exchange necessary to maintain aerobic metabolism. Thus, extracorporeal membrane oxygenation is an acceptable technique in the management of neonates with respiratory distress syndrome. In adults, all three techniques are still experimental but have promise. The development of a totally artificial lung remains some time away. DAVID M. GELMONT, MD South Pasadena, California
REFERENCES Anderson HL III, Delius RE, Sinard JM, et al: Early experience with the adult extracorporeal membrane oxygenation in the modem era. Ann Thorac Surg 1992; 53:553-563 Lally KP, Clark R, Schebdeman C, et al: Extracorporeal membrane oxygenation in the newbom. Milit Med 1990; 155:377-379
Bronchiolitis Obliterans Organizing Pneumonia THE TERM bronchiolitis obliterans organizing pneumonia (BOOP) was coined in 1985 to describe a lung disease characterized histologically by the presence of intraluminal fibroblastic proliferation. In Europe, BOOP is also known as cryptogenic organizing pneumonitis. It has recently been suggested that the disorder be renamed as cryptogenic intramural fibrosis of distal air spaces. Bronchiolitis obliterans organizing pneumonia is divided into primary or idiopathic and secondary. The secondary BOOP may occur in association with certain infections-
with Legionella, Mycoplasma, or Adenovirus species-the inhalation oftoxic gases (nitrogen dioxide), graft-versus-host disease in bone marrow and heart-lung transplant recipients, and collagen vascular diseases. It is, however, the idiopathic or primary BOOP that enters in the differential diagnosis of diffuse interstitial lung disease. Because of certain common clinical and physiologic abnormalities, BOOP is often misdiagnosed as idiopathic pulmonary fibrosis, sarcoidosis, pneumoconiosis, hypersensitivity pneumonitis, or chronic eosinophilic pneumonia. It is important that BOOP, because of its benign course and favorable response to corticosteroids, is not overlooked or misdiagnosed. Idiopathic BOOP occurs mainly in adults, with a peak incidence in the sixth decade; women and men are affected equally. Most patients have a subacute illness with cough, dyspnea, fever, and fatigue of a few weeks' duration. The patient's sedimentation rate is often elevated. Although auscultation may reveal rales, in a third of patients the results of a pulmonary examination are normal. Hypoxemia occurs in almost all patients. Lung volumes are reduced, but airway obstruction is not a feature. Diffusing capacity is impaired. Chest roentgenograms show bilateral patchy airspace densities, commonly in peripheral areas, and many other radiographic patterns have also been reported. Honeycombing is rare. The conventional and high-resolution computed tomographic scan findings are nonspecific, but these new techniques are helpful in distinguishing BOOP from idiopathic pulmonary fibrosis and granulomatous lung disease. On histologic examination, the lungs display immature-appearing plugs in the respiratory bronchioles, alveolar ducts, and peribronchial alveolar spaces. The alveolar spaces also contain foamy cells reflecting the proximal airway obstruction. Alveolar septa are thickened and contain mononuclear cell infiltrate. The presence of intraluminal plugs of fibroblasts, however, distinguishes BOOP not only from idiopathic pulmonary fibrosis but also from other interstitial lung disorders. When should a clinician think about a diagnosis of bronchiolitis obliterans organizing pneumonia? Internists and pulmonologists should consider including BOOP in the differential diagnosis of a subacute interstitial pneumonia, particularly when the patient has influenza-like features with cough, dyspnea, fever, malaise, and weight loss. A poor or unsatisfactory response to antibiotics is another feature favoring this diagnosis. A good transbronchial lung biopsy specimen in conjunction with a strongly suggestive clinical history and examination is in many cases adequate to establish the diagnosis. An open-lung biopsy is needed when a transbronchial biopsy fails to establish the diagnosis. This pneumonia has an excellent prognosis. It responds well to corticosteroids; almost two thirds ofthe patients in one study improved with the use of corticosteroids. Fewer than 5% of patients die of respiratory failure. Idiopathic bronchiolitis obliterans organizing pneumonia was recently added to the long list of interstitial disorders. The disease has a benign course with an excellent response to corticosteroids, but we remain ignorant of its cause. OM P. SHARMA, MD Los Angeles, California
REFERENCES Bellomo R, Finlay M, McLaughlin P, Tai E: Clinical spectrum of cryptogenic organizing pneumonitis. Thorax 1991; 46:554-558
