EPITOMES-CHEST DISEASES
170
agents to be Streptococcus pneumoniae (15.3%), Haemophilus influenzae (10.9%), Legionella species (6.7%), and Chlamydia pneumoniae (6.1%). These findings strongly support including erythromycin in the empiric antibiotic treatment of community-acquired pneumonia. Two new macrolide antibiotics, clarithromycin and azithromycin, may be better tolerated and as effective as erythromycin in treating legionella, chlamydial, and mycoplasmal infections, although they are sevenfold more expensive. Other pathogens responsible for community-acquired pneumonia are more common in specific patients. Staphylococcus aureus is observed in nursing home residents and following influenza infection. Moraxella (Branhamella) catarrhalis causes pneumonia in older patients and those with obstructive lung disease. Erythromycin generally is effective as the initial empiric therapy for infection with these organisms. More specific therapy for M catarrhalis and H influenzae includes the combination drugs amoxicillin and potassium clavulanate, ampicillin and sulbactam sodium, trimethoprim and sulfamethoxazole, ciprofloxacin, or a thirdgeneration cephalosporin. Aerobic gram-negative bacilli are seen more commonly in older patients, those who use alcohol, and those with obstructive lung disease. Ciprofloxacin is not an ideal choice for empiric coverage of pneumonia because of marginal activity against S pneumoniae. In a severely ill or immunocompromised patient with community-acquired pneumonia of unknown origin, gram-negative bacilli must be covered. Most pneumonias that develop in immunocompromised and hospital patients are caused by aerobic gram-negative bacilli. The most common agents are those of the family Enterobacteriaceae-Klebsiella pneumoniae, Escherichia coli, Enterobacter species, and Serratia marcescens-and Pseudomonas species. Several third-generation cephalosporins have excellent activity against these organisms and are good choices for these patients. Current evidence continues to support using a semisynthetic penicillin (piperacillin sodium) or a third-generation cephalosporin (ceftazidime) in synergistic combination with an aminoglycoside to treat pseudomonad infections. S aureus may be seen in the nosocomial setting and should be covered with initial therapy or if gram-positive cocci are observed in pulmonary secretions. Many third-generation cephalosporins such as ceftizoxime provide S aureus coverage. If methicillin-resistant S aureus is present in the hospital, vancomycin hydrochloride should be used in initial empiric regimens. Aspiration pneumonia occurring in the community may be treated effectively with penicillin, but the increasing incidence of resistant Bacteroides species makes clindamycin hydrochloride a more reliable choice. Patients in hospital have high rates of colonization of the oropharynx and gastrointestinal tract with gram-negative bacilli. Antibiotic therapy for aspiration in the hospital must cover the usual nosocomial organisms as well as anaerobic pathogens; monotherapy with a third-generation cephalosporin such as ceftizoxime is reasonable empiric coverage. Pneumonia caused by Pneumocystis carinii, viruses, and fungi (Aspergillus species, Candida species) may also develop in immunocompromised patients, requiring agents not typically included in initial empiric regimens. A recent randomized trial has shown that therapy with broad-spectrum antibiotics plus trimethoprim-sulfamethoxazole and erythromycin was as effective as and caused fewer complications
than open-lung biopsy in cancer patients with diffuse pulmonary infiltrates. It is accepted practice to add empiric antifungal therapy for neutropenic patients who do not respond to treatment with antibacterial agents after several days. In all settings, when a specific etiologic agent is identified, antimicrobial therapy should be narrowed to avoid superinfection and the selection of drug-resistant bacteria. With regard to preventing nosocomial pneumonia in critically ill patients, a recent well-controlled study has shown that selective decontamination of the digestive tract does not improve survival in intubated patients receiving mechanical ventilation in intensive care units. MICHAEL S. BERNSTEIN, MD San Francisco, California
REFERENCES Browne MJ, Potter D, Gress J, et al: A randomized trial of open lung biopsy versus empiric antimicrobial therapy in cancer patients with diffuse pulmonary infiltrates. J Clin Oncol 1990; 8:222-229 Fang GD, Fine M, Orloff J, et al: New and emerging etiologies for communityacquired pneumonia with implications for therapy-A prospective multicenter study of 359 cases. Medicine (Baltimore) 1990; 69:307-316 Gastinne H, Wolff M, Delatour F, Faurisson F, Chevret S: A controlled trial in intensive care units of selective decontamination of the digestive tract with nonabsorbable antibiotics. N Engl J Med 1992; 326:594-599 Neu HC: New macrolide antibiotics: Azithromycin and clarithromycin. Ann Intern Med 1992; 116:517-519
Diagnosis of Pulmonary Embolism THE ACrUAL INCIDENCE and natural history of pulmonary embolism are unknown. Perhaps 30% of patients are symptomatic and have substantial morbidity and mortality. Diagnosis is essential because treatment is thought to reduce mortality. Symptoms and signs are nonspecific, and examination of leg veins is helpful only infrequently. Pulmonary angiography is the gold standard for diagnosis but is invasive, often inconvenient, and, in some institutions, done too infrequently to approach the accuracy reported from major centers. Noninvasive screening includes radionuclide lung scanning and examination of the leg veins by impedance plethysmography and duplex ultrasonography. The positive predictive value of any test, however, is a function of the clinical probability that the condition exists. Lung scanning is an excellent screening test. A normal scan predicts with almost 100% probability that pulmonary embolism has not occurred. Contrariwise, a high-probability scan is associated with thromboembolism in 50% to 90% of patients. The probability of a true-positive is a function of the clinical science probability. Unfortunately, a high-probability scan is seen in only 10% to 15% of patients and is, therefore, nonsensitive. The dilemma is how to proceed when the scan is intermediate, indeterminate, or of low probability in a patient with at least a moderate risk for pulmonary embolism. A useful approach is to examine the leg veins with impedance plethysmography or duplex ultrasonography. The sensitivity and specificity of these tests in patients with symptoms of deep-vein thrombosis is reported to be in excess of 90%. In asymptomatic patients after a hip operation, impedance plethysmography was found to have an unacceptably low sensitivity of 24%. Another series found that 30% of patients with angiographically demonstrated pulmonary emboli had normal leg venograms. If a patient has a moderate likelihood of pulmonary embolism, an intermediate- or low-probability scan, and negative leg vein studies, do we proceed with pulmonary angiography or do we observe? A report from Canada suggests that if leg
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
170
agents to be Streptococcus pneumoniae (15.3%), Haemophilus influenzae (10.9%), Legionella species (6.7%), and Chlamydia pneumoniae (6.1%). These findings strongly support including erythromycin in the empiric antibiotic treatment of community-acquired pneumonia. Two new macrolide antibiotics, clarithromycin and azithromycin, may be better tolerated and as effective as erythromycin in treating legionella, chlamydial, and mycoplasmal infections, although they are sevenfold more expensive. Other pathogens responsible for community-acquired pneumonia are more common in specific patients. Staphylococcus aureus is observed in nursing home residents and following influenza infection. Moraxella (Branhamella) catarrhalis causes pneumonia in older patients and those with obstructive lung disease. Erythromycin generally is effective as the initial empiric therapy for infection with these organisms. More specific therapy for M catarrhalis and H influenzae includes the combination drugs amoxicillin and potassium clavulanate, ampicillin and sulbactam sodium, trimethoprim and sulfamethoxazole, ciprofloxacin, or a thirdgeneration cephalosporin. Aerobic gram-negative bacilli are seen more commonly in older patients, those who use alcohol, and those with obstructive lung disease. Ciprofloxacin is not an ideal choice for empiric coverage of pneumonia because of marginal activity against S pneumoniae. In a severely ill or immunocompromised patient with community-acquired pneumonia of unknown origin, gram-negative bacilli must be covered. Most pneumonias that develop in immunocompromised and hospital patients are caused by aerobic gram-negative bacilli. The most common agents are those of the family Enterobacteriaceae-Klebsiella pneumoniae, Escherichia coli, Enterobacter species, and Serratia marcescens-and Pseudomonas species. Several third-generation cephalosporins have excellent activity against these organisms and are good choices for these patients. Current evidence continues to support using a semisynthetic penicillin (piperacillin sodium) or a third-generation cephalosporin (ceftazidime) in synergistic combination with an aminoglycoside to treat pseudomonad infections. S aureus may be seen in the nosocomial setting and should be covered with initial therapy or if gram-positive cocci are observed in pulmonary secretions. Many third-generation cephalosporins such as ceftizoxime provide S aureus coverage. If methicillin-resistant S aureus is present in the hospital, vancomycin hydrochloride should be used in initial empiric regimens. Aspiration pneumonia occurring in the community may be treated effectively with penicillin, but the increasing incidence of resistant Bacteroides species makes clindamycin hydrochloride a more reliable choice. Patients in hospital have high rates of colonization of the oropharynx and gastrointestinal tract with gram-negative bacilli. Antibiotic therapy for aspiration in the hospital must cover the usual nosocomial organisms as well as anaerobic pathogens; monotherapy with a third-generation cephalosporin such as ceftizoxime is reasonable empiric coverage. Pneumonia caused by Pneumocystis carinii, viruses, and fungi (Aspergillus species, Candida species) may also develop in immunocompromised patients, requiring agents not typically included in initial empiric regimens. A recent randomized trial has shown that therapy with broad-spectrum antibiotics plus trimethoprim-sulfamethoxazole and erythromycin was as effective as and caused fewer complications
than open-lung biopsy in cancer patients with diffuse pulmonary infiltrates. It is accepted practice to add empiric antifungal therapy for neutropenic patients who do not respond to treatment with antibacterial agents after several days. In all settings, when a specific etiologic agent is identified, antimicrobial therapy should be narrowed to avoid superinfection and the selection of drug-resistant bacteria. With regard to preventing nosocomial pneumonia in critically ill patients, a recent well-controlled study has shown that selective decontamination of the digestive tract does not improve survival in intubated patients receiving mechanical ventilation in intensive care units. MICHAEL S. BERNSTEIN, MD San Francisco, California
REFERENCES Browne MJ, Potter D, Gress J, et al: A randomized trial of open lung biopsy versus empiric antimicrobial therapy in cancer patients with diffuse pulmonary infiltrates. J Clin Oncol 1990; 8:222-229 Fang GD, Fine M, Orloff J, et al: New and emerging etiologies for communityacquired pneumonia with implications for therapy-A prospective multicenter study of 359 cases. Medicine (Baltimore) 1990; 69:307-316 Gastinne H, Wolff M, Delatour F, Faurisson F, Chevret S: A controlled trial in intensive care units of selective decontamination of the digestive tract with nonabsorbable antibiotics. N Engl J Med 1992; 326:594-599 Neu HC: New macrolide antibiotics: Azithromycin and clarithromycin. Ann Intern Med 1992; 116:517-519
Diagnosis of Pulmonary Embolism THE ACrUAL INCIDENCE and natural history of pulmonary embolism are unknown. Perhaps 30% of patients are symptomatic and have substantial morbidity and mortality. Diagnosis is essential because treatment is thought to reduce mortality. Symptoms and signs are nonspecific, and examination of leg veins is helpful only infrequently. Pulmonary angiography is the gold standard for diagnosis but is invasive, often inconvenient, and, in some institutions, done too infrequently to approach the accuracy reported from major centers. Noninvasive screening includes radionuclide lung scanning and examination of the leg veins by impedance plethysmography and duplex ultrasonography. The positive predictive value of any test, however, is a function of the clinical probability that the condition exists. Lung scanning is an excellent screening test. A normal scan predicts with almost 100% probability that pulmonary embolism has not occurred. Contrariwise, a high-probability scan is associated with thromboembolism in 50% to 90% of patients. The probability of a true-positive is a function of the clinical science probability. Unfortunately, a high-probability scan is seen in only 10% to 15% of patients and is, therefore, nonsensitive. The dilemma is how to proceed when the scan is intermediate, indeterminate, or of low probability in a patient with at least a moderate risk for pulmonary embolism. A useful approach is to examine the leg veins with impedance plethysmography or duplex ultrasonography. The sensitivity and specificity of these tests in patients with symptoms of deep-vein thrombosis is reported to be in excess of 90%. In asymptomatic patients after a hip operation, impedance plethysmography was found to have an unacceptably low sensitivity of 24%. Another series found that 30% of patients with angiographically demonstrated pulmonary emboli had normal leg venograms. If a patient has a moderate likelihood of pulmonary embolism, an intermediate- or low-probability scan, and negative leg vein studies, do we proceed with pulmonary angiography or do we observe? A report from Canada suggests that if leg
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
