Pulmonary Physiology during Pulmonary Embolism* C. Gregory EUiott, M.D., F.C.C.P.
Acute pulmonary thromboembolism produces a number of pathophysiologic derangements of pulmonary function. Foremost among these alterations is increased pulmonary vascular resistance. For patients without preexistent cardiopulmonary disease, increased pulmonary vascular resistance is directly related to the degree ofvascular obstruction demonstrated on the pulmonary arteriogram. Vasoconstriction, either re8ex1y or biochemically mediated, may contribute to increased pulmonary vascular resistance. Acute pulmonary thromboembolism also disturbs matching of ventilation and blood Row. Consequently, some lung units are overventilated relative to perfusion (increased dead space), while other lung units are underventilated relative to perfusion (venous admixture). True right-to-Ieft shunting of mixed venous blood can occur through the lungs (intrapulmonary shunt) or across the atrial septum (intracardiac shunt). In addition, abnormalities of pulmonary gas exchange (carbon monoxide transfer), pulmonary compliance and airway resistance, and ventilatory control may accompany pulmonary embolism. Thrombolytic therapy can reverse the hemodynamic derangements of acute pulmonary thromboembolism more rapidly than anticoagulant therapy. Limited data suggest a sustained bene6t of thrombolytic treatment on the pathophysiologic alterations of pulmonary vascular resistance and pulmonary gas exchange produced by acute pulmonary emboli.
ulmonary physiologic alterations remain important P indicators of the presence and severity of pulmo-
terioles «100 JLm in diameter), and pulmonary capillaries.' The media of large pulmonary arteries contains elastic fibrils with some smooth muscle fibers. In contrast, the muscular pulmonary arteries contain circularly oriented smooth muscle, bounded by internal and external elastic laminae, and the arterioles contain a single elastic lamina with no muscular media (Fig 1). The elastic character of the normal pulmonary arterial tree allows for substantial increases of blood flow without proportional increase of pulmonary artery pressure. This distensible property of the pulmonary artery tree permits adaptation to conditions characterized by increased pulmonary blood Sow. Investigators have described normal pulmonary artery pressures when pulmonary blood Sow is twice normal in the setting of atrial septal defects" and months following pneumonectomy" Whether the elastic properties of pulmonary arteries provide any compensation for vascular obstruction in the setting of acute pulmonary embolism remains less certain. Pulmonary artery pressure and pulmonary vascular resistance increase proportionately to the increased Sow when a main pulmonary artery is acutely obstructed by inflation of a balloon catheter(Fig 2). This maneuver most closely mimics the acute physiologic response to the obstruction produced by
nary thromboembolism. The abrupt increase in pulmonary vascular resistance that accompanies massive pulmonary emboli is the principal cause of death from this disease. Thrombolytic therapy, unlike heparin therapy, can acutely reverse many of the pathophysiologic effects of pulmonary emboli. Therefore, an understanding of the physiologic consequences of acute pulmonary embolism and the influence of thrombolysis on the pathophysiology of pulmonary embolism is useful (Table 1). HEMODYNAMICS
Normal Pulmonary Arteries
The normal pulmonary arterial tree consists oflarge elastic arteries (>1,000 JLm in external diameter), smaller muscular pulmonary arteries, pulmonary ar ·From the Pulmonary Division and Department of Medicine, LDS Hospital and University of Utah School of Medicine, Salt Lake City. Reprint requests: Dr. EUIott, EUlmonary Division, WS Hospital, 8th Avenue and C Street , Salt Lake CUy, ur 84143.
FIGURE 1. Transverse section of a normal pulmonary artery demonstrates internal and external elastic lining enclosing a thin muscular media (elastic-van Gieson; X 168). (From reference 1. Reproduced by permission.) CHEST I 101 I 4 I APRIl, 1992 I Supplement
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Table 1- PulmontwrI Plagaiologg during Acute Basic Physiology
Effect of Thromboembolism
Increased pulmonary vascular resistance
Hemodynamics
Increased alveolar dead space Hypoxemia
Gas exchange
Ventilatory control Airway resistance Pulmonary compliance Pulmonary infarction
Impaired carbon monoxide transfer Alveolar hyperventilation Increased airway resistance Decreased pulmonary compliance Obstructive pulmonary arterial oxygen 80w
thromboembolism. It suggests that vascular distention does little to compensate for the reduction of the vascular cross-sectional area that accompanies acute pulmonary embolism.
Increased Pulmonary Vascular Resistance Pulmonary thromboembolism acutely increases pulmonary vascular resistance. Mean pulmonary artery pressure increases in proportion to the degree of pulmonary vascular obstruction in patients without preexistent pulmonary vascular disease (Fig 3). Abnormal increases of pulmonary artery pressure are likely when angiographically demonstrable obstruction exceeds 25% to 30% of the pulmonary arterial tree. Mean pulmonary artery pressures of 30 to 40 20
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when a balloon occludes the right main branch of the pulmonary artery. These measurements illustrate the failure of elastic pulmonary vessels to distend in the setting of acute vascular obstroction. (From reference 1. Reproduced by pennission.)
1845
PulmontwrI Emboliam Mechanism
Vascular obstruction Vasoconstriction by vasoactive amines Vasoconstriction by barore8ex Vascular obstruction Alveolar hypoventilation LowVIQ units Rigbt-to-left shunt Intracardiac Intrapulmonary Loss of gas exchange surface? Reftex stimulation of irritant receptors Bronchoconstriction Lung edema and hemorrhage, loss of surfactant Infarction requires additionalimpairment of oxygen supply
Reference
5 6-9 1()"12
19 14,15
22
27,30 29 36,37
38 39-43 45,46 49-53
mm Hg represent severe pulmonary hypertension for the previously healthy patient because 40 mm Hg is approximately the maximum pressure that a previously normal right ventricle can generate." In contrast, patients with acute pulmonary embolism superimposed on chronic pulmonary vascular disease have higher pulmonary artery pressures because of right ventricular hypertrophy In 1 series of patients, 5 a mean pulmonary artery pressure of 40 mm Hg was average for patients with preexistent pulmonary vascular disease. Furthermore, no correlation exists between the degree of obstruction of the pulmonary artery tree (scored from pulmonary arteriograms) and the mean pulmonary artery pressure (Fig 4). Vasoactive amines such as serotonin and thromboxane ~ may contribute to the development of pulmonary hypertension following acute pulmonary embolism. Serotonin causes contractions of isolated canine pulmonary arteries, which serotonergic antagonists reverse." Thromboemboli do not contain vasoactive amines, but experimental emboli harvested from the lungs of New Zealand white rabbits have aggregated platelets adherent to their surface," Such platelets are rich sources of serotonin. Furthermore, pretreatment with heparin reduces the numbers of platelets adherent to thrombi. Huval et al8 described dramatic reductions of mean pulmonary artery pressure and pulmonary vascular resistance when ketanserin (a selective serotonin antagonist) was administered to dogs that had been embolized by autologous clot," However, infusion of ketanserin into patients with acute pulmonary embolism produces small reductions in mean pulmonary artery pressure and pulmonary vascular resistance." Baroreceptors are present in pulmonary arteries. 10,11 Pressure exerted against the wall of the pulmonary artery by blood flowing past an obstructing clot or by increased pulmonary artery pressure may induce reflex vasoconstriction. Inflation of a balloon catheter in conscious dogs increases pulmonary artery pressure Pulmonary Physiology during Pulmonary Embolism (c. Gt8gory ElIott)
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Increased Alveolar Dead Space A major pathophysiologic consequence of acute pulmonary embolism is an increased alveolar dead space (Vd). This occurs because lung units continue to be ventilated in spite of diminished or absent perfusion. Complete vascular obstruction by an embolus causes an increase in absolute dead space (y/ Q= 00). In contrast, incomplete obstruction of a pulmonary artery (ie, increased ventilation relative to perfusion) increases physiologic dead space by increasing ratios of ventilation relative to blood How of involved lung units. These effects impair the efficient elimination of CO 2 by the lung. Although pulmonary emboli impair efficient pulmonary elimination of CO 2 , hypercapnia and respiratory acidosis rarely accompany pulmonary embolism .14,15 This presumably reflects the fact that compensatory hyperventilation eliminates CO 2 in all but the most extensive thromboemboli. In cases with a sufficient degree of vascular obstruction to produce hypercapnia, the hemodynamic sequelae ofacute right ventricular failure usually prove fatal. If the patient survives, the low cardiac output syndrome that results from right heart failure increases -c a:
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Hypoxemia Decreased Pa02and increased alveolar-arterial oxygen tension gradient (P[A-a]OJ commonly accompany acute pulmonary embolism. m.21 However, acute pulmonary embolism can occur with normal Pa02or P(Aa)02. iO The Pa02 often remains normal because hyperventilation lowers PAC02, with a resultant increase ofPA02 • Clinical studies have demonstrated a normal Pa02 in up to 26% of patients with angiographically documented thromboembolt." Calculation ofP(A-a)02 provides a more sensitive measurement of the impaired oxygen transfer associated with acute pulmonary embolismoo•22 because the effects of hypocapnia are considered. A number of factors contribute to the severity of arterial hypoxemia that accompanies acute pulmonary embolism. Preexistent cardiopulmonary disease, a common predisposition for pulmonary embolism, frequently produces arterial hypoxemia. When patients without prior cardiopulmonary disease are studied, a direct relationship is demonstrated between the percentage of pulmonary vasculature obstructed and the measured Pa02 . 23 Other factors that may contribute include reflex bronchoconstriction, atelectasis or infarction of lung tissue,24-16 and the presence of a patent foramen ovale. f:7 Mismatching of ventilation and perfusion, intracardiac and/or intrapulmonary shunting of mixed venous blood, and alveolar hypoventilation each may contribute to a reduced Pa02 following pulmonary embolism. Normal lungs match ventilation to blood flow More than 90% of the cardiac output passes through lung units with 0.1 S V/Q S 10.22 Experimental pulmonary embolism redistributes pulmonary blood flo~ producing low and very high V/Q units (Fig 5). In selected patients with more than 50% of the pulmonary vascular bed obstructed by thromboemboli, substantial rightto-left shunting of mixed venous blood occurs." This increased shunt fraction may represent perfusion of unventilated lung units (V/Q=O) due to atelectasis, or it may result from right ventricular failure accompanied by a patent foramen ovale. 27 •29 •30 In either situa1888
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5. Experimental pulmonary emboli change the normal
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matching of ventilation and perfusion. Neither absolute shunt nor dead space ventilation increases. (From reference 22. Reproduced by permission.)
tion, or in the setting of low V/Q units, reduction of mixed venous POI consequent to low cardiac output further decreases the reduced Pa0l by presenting the pulmonary capillary with a lower P02 . 31 In rare circumstances, an increased PaC02 due to massive pulmonary embolism and ventilatory failure contributes to arterial hypoxemia. Hypoxemia results because the rising PAC02 lowers PAO!, thus decreasing the driving pressure for oxygen transport across the lungs. Differentiation of the pathophysiologic mechanism that is responsible for arterial hypoxemia can guide therapeutic interventions. Arterial hypoxemia caused by mismatching of ventilation and perfusion is easily corrected by the administration oflow-8ow oxygen. In contrast, low-flow oxygen does not correct arterial Pulmonary Physiology during Pulmonary Embolism (c.
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hypoxemia caused by shunting of mixed venous blood 01IQ = 0). Administration of high Bows of gas mixtures with a high inspired oxygen fraction may adequately support patients with high right-to-left shunt fractions. However, in some instances severe atelectasis causes intrapulmonary shunting of mixed venous blood. Continuous positive airway pressure (CPAP) or positive end-expiratory pressure (PEEP) can increase Pa02 by distending airways.29 Paradoxically if increased pulmonary vascular resistance causes right ventricular failure and intracardiac shunting through a patent foramen ovale, the administration of positive airway pressure (CPAP or PEEP) can increase right ventricular afterload and decrease cardiac output, further decreasing Pa02 • In this setting, correction of arterial hypoxemia is best achieved by reducing right ventricular afterload with therapy such as thrombolysis.j" Alveolar hypoventilation (increased PaCOJ rarely contributes substantially to arterial hypoxemia associated with pulmonary embolism, and usually reflects massive embolism accompanied by severe increases of VdNt and the failure of ventilatory muscles to sustain the compensatory marked increases of minute ventilation. In this setting, positive-pressure ventilation and paralysis to decrease CO 2 production may help until the vascular obstruction can be relieved.
resistances to CO transfer do not necessarily represent anatomic structures. Comparison of morphometric measurements of OLeo with physiologic measurements of DLeo reveal wide discrepancies. The OM and 8 Vc are of approximately equal size when measured physiologically, whereas morphometric D M is about 6 times the size of morphometric 9 Vc.33 Physiologic measurements suggest that OM and Vc contribute equally to DLeo, whereas morphometric determinants suggest that Vc is the major determinant of DLeo. Thus, 8 Vc is best considered that part of the DLeo that varies with hemoglobin and inspired oxygen fraction, and D M is best considered the remaining resistance to CO transfer that is not influenced by hemoglobin or inspired oxygen fraction. 34 •3S Few measurements ofDLeo are available following acute pulmonary thromboembolism.P" The DLco is usually decreased. Sharma et al37 reported measurements of Vc for 40 patients who suffered acute pulmonary embolism. These patients had no prior history of cardiopulmonary disease. Comparison of patients who received heparin with those treated with thrombolytic agents showed significantly greater Vc for the lytic therapy group 1 year after the acute pulmonary embolus (Fig 7).
Carbon Monoxide Transfer
Normal ventilatory control depends on the interaction of sensors and respiratory muscles. The sensors include (1) central chemoreceptors, located on the brain-stem surface, which respond to CO 2 and hydrogen ion concentration; (2) peripheral chemoreceptors, located adjacent to the carotid arteries, which respond primarily to decreased arterial Po 2 ; and (3) proprioceptors, located in lung tissue and muscle spindles of diaphragm, intercostal, and abdominal muscle groups, which respond to stretch and irritation. Hyperventilation commonly accompanies acute pulmonary embolism.P The increased minute ventilation usually leads to hypocapnia and respiratory alkalosis, The mechanisms that lead to alveolar hyperventilation following pulmonary embolism are undefined. However, correction of hypoxemia with supplemental oxygen seldom reverses respiratory alkalosis, suggesting that proprioceptors are important contributors to hyperventilation associated with pulmonary emboli. Limited data suggest that irritant and juxtacapillary sensors contribute to the reflex stimulation of ventilation by pulmonary emboli."
The pulmonary diffitsion capacity for carbon monoxide (DLeo) measures the amount of CO transferred from alveolar gas to pulmonary capillary blood per minute for each millimeter of mercury of CO driving pressure. In 1957, Roughton and Forsterw derived a relationship of physiologic factors that influence DLeo. Three factors that affect CO diffusion include (1) the resistance offered by the membranes (DM); (2) the volume of blood in the pulmonary capillaries (Ve), and (3) the volume of CO that each milliliter of blood will take up for each millimeter of mercury of pressure (8). The relation that Roughton and Forster derived for these variables is as follows: lIDLeo = 1/9 Vc + l/DM.
Pulmonary capillary blood volume 01c) is determined by measuring DLeo several times at widely different inspired oxygen concentrations. The differing oxygen concentrations change the number of milliliters of oxygen bound to hemoglobin in pulmonary capillary blood and thus change 8. A plot of the reciprocals of the measured DLeo and 8 pairs allows a line to be fit by least squares. Since the relationship I/DLco = 1/8 Vc + I/DM is a linear equation (y =mx + b), where l/DM = b is the y intercept and 11 Vc = m is the slope, Vc is the reciprocal of the slope plotted from repeated measurements of DLeo at varying inspired oxygen fractions (Fig 6). .An important concept is that these physiologic
VENTILATORY CONTROL
AIRWAY RESISTANCE
The resistance to airflow is an important determinant of the work of breathing. AiJway resistance is critically dependent on lung volume and the radius of the conducting airways. A number of clinical and experimental observations suggest that airway resisCHEST I 101 I 4 I APRIL. 1992 I SUpplement
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tance may increase following pulmonary emboli;39-43 however, direct measurements of airway resistance in humans following well-documented acute pulmonary embolism are not readily available. Clinicians have described wheezing acutely following pulmonary emboli.'" Furthermore, experimental models of acute pulmonary embolism demonstrate that airway con-
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striction occurs adjacent to the embolized lung segment. For example, Thomas et al40 demonstrated that airway resistance increases following embolization of autologous thrombi to dog lungs. Available evidence suggests that serotonin mediates the bronchoconstrtction that accompanies thromboembolism. 39 •40 .
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7. Pulmonary capillary blood volume (Vc) is greater for thrombolytic-treated patients than for heparin-treated (H) patients when measured 2 and 52 weeks after acute pulmonary embolism. (From reference 37. Reproduced by permission.) FIGURE
188S
Pulmonary Physiology during Pulmonary Embolism (C. GI8fIOrY EllIott)
COMPLIANCE
Pulmonary compliance is another important determinant of the work of breathing. The total compliance of lungs is decreased by pulmonary edema, fibrosis, and atelectasis. As is the case with airway resistance, both clinical and experimental observations suggest that the pressure-volume characteristics of lungs are altered by acute pulmonary embolism, but direct measurements of pulmonary compliance following well-documented acute pulmonary embolism are not readily available. 41,a In experimental models of total pulmonary artery occlusion, loss of pulmonary surfactant develops distal to the occlusion. 45 ,46 Atelectasis and edema result. Furthermore, clinicians have described the development of pulmonary edema when acute thromboemboli are lysed. 41 ,48 Such edema presumably results from reperfusion injury to the alveolar capillary bed. Thus, several lines of evidence suggest that acute pulmonary embolism can decrease pulmonary compliance. PULMONARY INFARCTION
Pulmonary infarction (ie, death of lung tissue distal to embolic obstruction) is an uncommon sequela of pulmonary thromboembolism.P'" The lung, unlike other tissues, has 3 sources of oxygen: (1) the pulmonary arteries, (2) the airways, and (3) bronchial arteries arising from the aorta or intercostobronchial trunk. In addition, nutrients may reach lung tissue distal to a pulmonary artery obstruction by retrograde How of oxygenated blood from the pulmonary veins. 52 Clinical and pathologic studies demonstrate that pulmonary infarction accompanies occlusion of small pulmonary arteries. SO,53 In contrast, occlusion or ligation ofcentral pulmonary arteries does not lead to pulmonary infarction because of the bronchial arterial blood supply 53 Dalen et al53 suggested. that pulmonary infarction results when smaller pulmonary arteries are 0bstructed and hemorrhage into the airways persists, In this scenario, the anastomotic channels that exist between distal bronchial arterioles and pulmonary arterioles allow bronchial arterial blood to enter the pulmonary capillary This blood extravasates into the alveolus. If clearance of alveolar blood is delayed for any reason (eg, left ventricular failure), then pulmonary infarction results. Advanced heart failure requiring vasodilator therapy was subsequently strongly associated with the occurrence of pulmonary infarction. 54 REVERSAL OF PULMONARY PATHOPHYSIOLOGY BY
THROMBOLYSIS
Thrombolytic therapy for acute pulmonary embolism can reverse the fundamental derangement of normal pulmonary physiology-obstruction of pulmonary arteries. However, secondary derangements
of pulmonary physiology, such as hypoxemia, are inconsistently affected by thrombolysis and, in some instances, may be adversely altered by reperfusion pulmonary edema. Thrombolysis provides reversal of the physiologic consequences of acute pulmonary embolism more rapidly heparin does. Measurements of pulmonary artery pressure and pulmonary vascular resistance, performed 24 to 72 h after the initiation of 6rst-generation thrombolytic agents (streptokinase, urokinase), demonstrate that small, but sigDmcantly greater, decreases of these parameters accompany thrombolysis. 55 ,56 The increase of PaOz was of marginal significance favoring thrombolysis. Second-generation thrombolytic agents (recombinant tissue plasminogen activator) produce similar hemodynamic effects within hours. 51 Quarititative scores of pulmonary angiograms and perfusion scans provide visual evidence of improved perfusion within 24 h after initiation of thrombolytic therap}T.51,58 In contrast to the rapid initial effect of thrombolytic drugs on pulmonary angiograms and scans, subsequent observations at 2 weeks and again at 1 year after the initiation of therapy demonstrate. no difference in the percentage of resolution of perfusion scans between heparin and thrombolytic drugs. 56 These observations raise the importantquestion ofwhether thrombolysis affects residual pathophysiologic alterations of lung function. Comparisons of patients who were randomly assigned. to treatment with thrombolytic therapy or heparin when acute pulmonary embolism was diagnosed demonstrate that physiologic abnor9nialities persist after heparin therapy Sharma et alsQ reported abnormal increases ofmean pulmonary artery pressure ·and pulmonary vascular resistance during exercise an average of 7 years after treatment ofacute pulmonary embolism. Furthermore, the same authors reported that treatment with urokinase or streptokinase was associated with significantly higher Vc measurements than were found with heparin 6 months after the acute pulmonary embolism."
than
SUMMARY
In summary, acute pulmonary embolism causes major pulmonary physiologic derangements. Understanding these alterations. may guide therapy Increased pulmonary vascular resistance results obstruction of the pulmonary arteries, and may result in acute right ventricular failure, hypotension mid death. This most important pathophysiologic de~e ment may be partially reversed by second-generation thrombolytic agents within hours of their administration. Arterial hypoxemia results from mismatching of ventilation and blood flow or from shunting of mixed venous blood. When hypoxemia is refractory to high inspired oxygen fractions (shunt), differentiation be-
from
CHEST I 101 I 4 I APRIL. 1992 I Supplement
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tween intrapulmonary and intracardiac shunting may direct therapy. Intrapulmonary shunt is reversed by CPA~ whereas CPAP may adversely affect intracardiac shunt. Relief of pulmonary artery obstruction by thrombolysis may correct hypoxemia resulting from intracardiac shunts. REFERENCES
1 Harris ~ Heath D. The human pulmonary circulation: its form and function in health and disease, 2nd ed. New York:ChurchillLivingstone, 1977; 22-30, 130 2 Craig RJ, Selzer A. Natural history and prognosis of atrial septal defect. Circulation 1968; 37:805-15 3 Cournand A, Riley RI, Himmelstein A, et al. Pulmonary circulation and alveolar ventilation-perfusion relationships after pneumonectomy. J Thorac Surg 1950; 19:80-116 4 Carlens E, Hanson HE, Nordenstrom B. Temporary unilateral occlusion of the pulmonary artery. J Thone Surg 1951; 22:52736 5 Sharma G, McIntyre KM, Shanna S, et aI. Clinical and hemodynamic correlates in pulmonary embolism. Clin Chest Med 1984; 5:421-28 6 McGoon MD, Van Houtte PM. Aggregating platelets contract isolated canine pulmonary arteries by releasing 5-hydroxytryptamine. J Clio Invest 1984; 74:828-33 7 Thomas D~ Gurewich ~ Ashford TR Platelet adherence to thromboemboli in relation to the pathogenesis and treatment of pulmonary embolism. N Eng) J Med 1966; 274:953-56 8 Huval ~ Mathieson MA, Stemp L], et al, Therapeutic benefits of 5-hydroxytryptamine inhibition foUowing pulmonary embo-lism. Ann Surg 1983; 197:3220-25 9 Huet Y, Brun-Buisson C, Lemaire F, et aI. Cardiopulmonary effects of ketanserin infusion in human pulmonary embolism. Am Rev Respir Dis 1987; 135:114-17 10 Coleridge JC, Kidd C. Electropbysiologic evidence of baroreceptors in the pulmonary artery of the dog. J Physiol 1960; 150:319-31 11 Vesity AM, Bevan KA. Distribution of nerve endings in the pulmonary artery of the cat. Science 1962; 135:785-86 12 Laks MM, Juratsch MS, Garver D, et al, Acute pulmonary artery hypertension produced by distention of the main pulmonary artery in the conscious dog. Cbest 1975; 68:807-13 13 Dantzker DR, Bower JS. Partial reversibility of chronic pulmonary hypertension caused by pulmonary thromboembolic disease. Am Rev Respir Dis 1981; 124:129-31 14 Bouchama A, Curley ~ Al-Dossary S, et aI. Refractory hypercapnia complicating massive pulmonary embolism. Am Rev Respir Dis 1988; 138:466-68 15 Haynes J8, Iseman MD. Massive pulmonary embolism presenting with hypercapnia and minimal intrapulmonary shunting. Rocky Mountain Med J 1979; 77:135-37 16 Riley RL, Permutt S, Said S, et al. Effect of posture on pulmonary dead space in man. J Appl Physioll959; 14:339-44 17 Rea HH, Withy JJ, Seelye ER, et ale The effects of posture on venous admixture and respiratory dead space in health. Am Rev Respir Dis 1977; 115:571-80 18 Baker R, Burld NK. The effects of alterations in ventilatory pattern on the ratio of dead space to tidal volume [abstract]. Chest 1982; 82:243 19 Burld NK. The dead space to tidal volume ratio in the diagnosis of pulmonary embolism. Am Rev Respir Dis 1986; 133:679-85 20 Critanic D, Merino PL. Improved use of arterial blood gas analysis in suspected pulmonary embolism. Chest 1989; 95:4851 21 Hoellerich VL, Wigton RS. Diagnosing pulmonary embolism using clinical findings. Arch Intern Med 1986; 146:1699-1704
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22 Dantzker DR, Bower JS. Alterations in gas exchange following pulmonary thromboembolism. Chest 1982; 81:495-501 23 McIntyre KM, Sasahara AA. The hemodynamic response to pulmonary embolism in patients without prior cardiopulmonary disease. Am 1 Cardio11971; 28:288-94 24 Levy SE, Simmons DH. Mechanism of arterial hypoxemia foUowing pulmonary thromboembolism in dogs. J Appl Physiol 1975; 39:41-6 25 Levy SEt Simmons DH. Redistribution of alveolar ventilation foUowing pulmonary thromboembolism in the dog. J Appl Physiol1974; 36:60-8 26 Severinghaus ~ Swanson E~ Finley J, et al. Unilateral bypoventilation produced by occlusion of one pulmonary artery. J Appl Pbysiol 1961; 16:53-60 Herve PH, Petitperez Simonneau G, et al. The mechanisms of abnormal gasexchange in acute massive pulmonary embolism [letter]. Am Rev Respir Dis 1983; 128:1101 28 D'Alonso GE, Bower IS, DeHart et aI. The mechanism of abnormal gas exchange in acute massive pulmonary embolism. Am Rev Respir Dis 1983; 128:170-72 29 D'Alonzo GE, Dantzker DR. The mechanisms of abnormal gas exchange in acute massive pulmonary embolism [letter]. Am Rev Respir Dis 1983; 128:1101-02 30 Shenoy MM, FriedmanSA, Dhar S, et aI. Streptokinase lysis of intraventricular thrombus and pulmonary emboli with resolution of acquired intracardiac shunt. Ann Intern Med 1985; 103:65-6 31 Manier G, Castaing Y, Guenard ,H. Determinants of hypoxemia during the acute phase of pulmonary embolism in bumans. Am Rev Respir Dis 1985; 132:332-38 32 Roughton FJ, Forster BE. Relative importance of diffusion and chemical reaction rates in determining rate of exchange of gases in the human lung, with special reference to true diffusing capacity of pulmonary membrane and volume of blood in the lung capillaries. J Appl Physioll957; 11:290-302 33 Crapo JD, Crapo RO. Comparison of total lung diffusion capacity and the membrane component of diffusion capacity as determined by physiologic and morphometric techniques. Respir Physioll983; 51:183-94 34 Forster RE II. The single-breath carbon monoxide transfer test 25 years on: a reappraisal-I. Physiological considerations [editorial]. Thorax 1983; 38:1 35 Crapo RO, Forster RE. Carbon monoxide diffusing capacity. Clio Chest Med 1989; 10:187-98 36 Bass H. Regional pulmonary function in patients with pulmonary embolism. BuU Physiopathol Respir 1970; 6:123-34 37 Shanna GVKR, Buleson VA, Sasahara AA. Effect oftbrombolytic therapy on pulmonary capillary blood volume in patients with pulmonary embolism. N Eng) J Med 1980;303:842-45 38 KeUey MAt Fishman AI! Pulmonary thromboembolic disease. In: Fishman ~ ed. Pulmonary diseases and disorders. New York: McGraw- Hill, 1988; 1062 39 Comroe JH, Van Lingen B, Stroud RC, et aI. Reftex and direct cardiopulmonary effects of 5-0H-tryptamine (serotonin): their possible role in pulmonary embolism and coronary thrombosis. Am J Physiol 1953; 173:379-86 40 Thomas D~ Stein M, Tonabe G, et aI. Mechanism ofbronchoconstriction produced by thromboemboli in dogs. Am J Physiol 1964; 206:1207-12 41 Gurewich ~ Thomas D~ Stein M, et aI. Broncboconstriction in the presence of pulmonary embolism. Circulation 1963; 27:33945 42 Dunn JS. The effects of multiple embolism of. pulmonary arterioles. Q J Med 1920; 13:129-47 43 Colp CR, WiUiams MH. Pulmonary function following pulmonary embolization. Am Rev Respir Dis 1962; 85:799-807 44 Moser KM. Pulmonary embolism. In: Murray JF, Nadel jA,
en
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Pulmonary Physiology during PumonaIy EmboIsm (C. Gregory EllIott)
45
46
47
48 49 50 51
52
eds. Textbook of respiratory medicine. Philadelphia: WB Saunders, 1988; 1308 Finley TH, Swensen E~ Clements jA, et ale Changes in mechanical properties, appearance and surface activity of extracts of one lung following occlusion of its pulmonary artery in the dog. Physiologist 1960; 3:56-72 Chernick ~ Hodson WA, Greenfield LJ. Effect of chronic pulmonary artery ligation on pulmonary mechanics and surfactant. J Appl Physioll966; 21:1815-19 Ward BJ, Pearse DB. Reperfusion pulmonary edema after thrombolytic therapy of massive pulmonary embolism. Am Rev Respir Dis 1988; 138:1308-11 MartinTR, Sandblom RJ, Johnson RJ. Adult respiratory distress syndrome following thrombolytic therapy for pulmonary embolism. Chest 1983; 83:151-53 Parker BM, Smith JR. Pulmonary embolism and infarction. Am J Med 1958; 24:402-27 Tsao MS, Schraufnagel D, Wong NS. Pathogenesis of pulmonary infarction. Am J Med 1982; 72:599-608 Freiman D, Wessler S, Lertzman W Experimental pulmonary embolism with serum-induced thrombi aged in vivo. Am J Patholl962; 39:95-104 Butler J, KowalskiTF, Willoughly S, et ale Preventing infarctions
53
54 55
56 57
58
59
after pulmonary artery occlusion [abstract]. Clio Res 1989; 37:163A Dalen JE, Heffakee CI, Alpert JS, et al. Pulmonary embolism, pulmonary hemorrhage, and pulmonary infarction. N Engl J Med 1977; 296:1431-35 Schraufnagel DE, Tsao MS, Vas IT, et aI. Factors associated with pulmonary infarction: a discriminant analysis study. Am JClio Patholl985; 84:15-8 Miller GA, Sutton GC, Kerr IH, et aI. Comparison of streptokinase and heparin in treatment of isolated acute massive pulmonary embolism. 8MJ 1971; 2:681-84 Hyers TM, Sasahara AA, Cole CM, et al. The urokinase pulmonary embolism trial. Circulation 1973; 47(suppl II): 4&-59 Goldhaber SZ, Kessler CM, Heit J, et ale Randomized controlled trial of recombinant tissue plasminogen activator versus urokinase in the treatment of acute pulmonary embolism. Lancet 1988; 2:293-98 Goldhaber SZ, Vaughan DE, Markis JE, et ale Acute pulmonary embolism treated with tissue plasminogen activator. Lancet 1986; 2:886-89 Sharma G~ Follend ED, McIntyre KM, et aI. Long-term hemodynamic benefit of thrombolytic therapy in pulmonary embolic disease [abstract]. J Am Coll Cardioll990; 15:65A
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Acute pulmonary thromboembolism produces a number of pathophysiologic derangements of pulmonary function. Foremost among these alterations is increased pulmonary vascular resistance. For patients without preexistent cardiopulmonary disease, increased pulmonary vascular resistance is directly related to the degree ofvascular obstruction demonstrated on the pulmonary arteriogram. Vasoconstriction, either re8ex1y or biochemically mediated, may contribute to increased pulmonary vascular resistance. Acute pulmonary thromboembolism also disturbs matching of ventilation and blood Row. Consequently, some lung units are overventilated relative to perfusion (increased dead space), while other lung units are underventilated relative to perfusion (venous admixture). True right-to-Ieft shunting of mixed venous blood can occur through the lungs (intrapulmonary shunt) or across the atrial septum (intracardiac shunt). In addition, abnormalities of pulmonary gas exchange (carbon monoxide transfer), pulmonary compliance and airway resistance, and ventilatory control may accompany pulmonary embolism. Thrombolytic therapy can reverse the hemodynamic derangements of acute pulmonary thromboembolism more rapidly than anticoagulant therapy. Limited data suggest a sustained bene6t of thrombolytic treatment on the pathophysiologic alterations of pulmonary vascular resistance and pulmonary gas exchange produced by acute pulmonary emboli.
ulmonary physiologic alterations remain important P indicators of the presence and severity of pulmo-
terioles «100 JLm in diameter), and pulmonary capillaries.' The media of large pulmonary arteries contains elastic fibrils with some smooth muscle fibers. In contrast, the muscular pulmonary arteries contain circularly oriented smooth muscle, bounded by internal and external elastic laminae, and the arterioles contain a single elastic lamina with no muscular media (Fig 1). The elastic character of the normal pulmonary arterial tree allows for substantial increases of blood flow without proportional increase of pulmonary artery pressure. This distensible property of the pulmonary artery tree permits adaptation to conditions characterized by increased pulmonary blood Sow. Investigators have described normal pulmonary artery pressures when pulmonary blood Sow is twice normal in the setting of atrial septal defects" and months following pneumonectomy" Whether the elastic properties of pulmonary arteries provide any compensation for vascular obstruction in the setting of acute pulmonary embolism remains less certain. Pulmonary artery pressure and pulmonary vascular resistance increase proportionately to the increased Sow when a main pulmonary artery is acutely obstructed by inflation of a balloon catheter(Fig 2). This maneuver most closely mimics the acute physiologic response to the obstruction produced by
nary thromboembolism. The abrupt increase in pulmonary vascular resistance that accompanies massive pulmonary emboli is the principal cause of death from this disease. Thrombolytic therapy, unlike heparin therapy, can acutely reverse many of the pathophysiologic effects of pulmonary emboli. Therefore, an understanding of the physiologic consequences of acute pulmonary embolism and the influence of thrombolysis on the pathophysiology of pulmonary embolism is useful (Table 1). HEMODYNAMICS
Normal Pulmonary Arteries
The normal pulmonary arterial tree consists oflarge elastic arteries (>1,000 JLm in external diameter), smaller muscular pulmonary arteries, pulmonary ar ·From the Pulmonary Division and Department of Medicine, LDS Hospital and University of Utah School of Medicine, Salt Lake City. Reprint requests: Dr. EUIott, EUlmonary Division, WS Hospital, 8th Avenue and C Street , Salt Lake CUy, ur 84143.
FIGURE 1. Transverse section of a normal pulmonary artery demonstrates internal and external elastic lining enclosing a thin muscular media (elastic-van Gieson; X 168). (From reference 1. Reproduced by permission.) CHEST I 101 I 4 I APRIl, 1992 I Supplement
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Table 1- PulmontwrI Plagaiologg during Acute Basic Physiology
Effect of Thromboembolism
Increased pulmonary vascular resistance
Hemodynamics
Increased alveolar dead space Hypoxemia
Gas exchange
Ventilatory control Airway resistance Pulmonary compliance Pulmonary infarction
Impaired carbon monoxide transfer Alveolar hyperventilation Increased airway resistance Decreased pulmonary compliance Obstructive pulmonary arterial oxygen 80w
thromboembolism. It suggests that vascular distention does little to compensate for the reduction of the vascular cross-sectional area that accompanies acute pulmonary embolism.
Increased Pulmonary Vascular Resistance Pulmonary thromboembolism acutely increases pulmonary vascular resistance. Mean pulmonary artery pressure increases in proportion to the degree of pulmonary vascular obstruction in patients without preexistent pulmonary vascular disease (Fig 3). Abnormal increases of pulmonary artery pressure are likely when angiographically demonstrable obstruction exceeds 25% to 30% of the pulmonary arterial tree. Mean pulmonary artery pressures of 30 to 40 20
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=
when a balloon occludes the right main branch of the pulmonary artery. These measurements illustrate the failure of elastic pulmonary vessels to distend in the setting of acute vascular obstroction. (From reference 1. Reproduced by pennission.)
1845
PulmontwrI Emboliam Mechanism
Vascular obstruction Vasoconstriction by vasoactive amines Vasoconstriction by barore8ex Vascular obstruction Alveolar hypoventilation LowVIQ units Rigbt-to-left shunt Intracardiac Intrapulmonary Loss of gas exchange surface? Reftex stimulation of irritant receptors Bronchoconstriction Lung edema and hemorrhage, loss of surfactant Infarction requires additionalimpairment of oxygen supply
Reference
5 6-9 1()"12
19 14,15
22
27,30 29 36,37
38 39-43 45,46 49-53
mm Hg represent severe pulmonary hypertension for the previously healthy patient because 40 mm Hg is approximately the maximum pressure that a previously normal right ventricle can generate." In contrast, patients with acute pulmonary embolism superimposed on chronic pulmonary vascular disease have higher pulmonary artery pressures because of right ventricular hypertrophy In 1 series of patients, 5 a mean pulmonary artery pressure of 40 mm Hg was average for patients with preexistent pulmonary vascular disease. Furthermore, no correlation exists between the degree of obstruction of the pulmonary artery tree (scored from pulmonary arteriograms) and the mean pulmonary artery pressure (Fig 4). Vasoactive amines such as serotonin and thromboxane ~ may contribute to the development of pulmonary hypertension following acute pulmonary embolism. Serotonin causes contractions of isolated canine pulmonary arteries, which serotonergic antagonists reverse." Thromboemboli do not contain vasoactive amines, but experimental emboli harvested from the lungs of New Zealand white rabbits have aggregated platelets adherent to their surface," Such platelets are rich sources of serotonin. Furthermore, pretreatment with heparin reduces the numbers of platelets adherent to thrombi. Huval et al8 described dramatic reductions of mean pulmonary artery pressure and pulmonary vascular resistance when ketanserin (a selective serotonin antagonist) was administered to dogs that had been embolized by autologous clot," However, infusion of ketanserin into patients with acute pulmonary embolism produces small reductions in mean pulmonary artery pressure and pulmonary vascular resistance." Baroreceptors are present in pulmonary arteries. 10,11 Pressure exerted against the wall of the pulmonary artery by blood flowing past an obstructing clot or by increased pulmonary artery pressure may induce reflex vasoconstriction. Inflation of a balloon catheter in conscious dogs increases pulmonary artery pressure Pulmonary Physiology during Pulmonary Embolism (c. Gt8gory ElIott)
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Increased Alveolar Dead Space A major pathophysiologic consequence of acute pulmonary embolism is an increased alveolar dead space (Vd). This occurs because lung units continue to be ventilated in spite of diminished or absent perfusion. Complete vascular obstruction by an embolus causes an increase in absolute dead space (y/ Q= 00). In contrast, incomplete obstruction of a pulmonary artery (ie, increased ventilation relative to perfusion) increases physiologic dead space by increasing ratios of ventilation relative to blood How of involved lung units. These effects impair the efficient elimination of CO 2 by the lung. Although pulmonary emboli impair efficient pulmonary elimination of CO 2 , hypercapnia and respiratory acidosis rarely accompany pulmonary embolism .14,15 This presumably reflects the fact that compensatory hyperventilation eliminates CO 2 in all but the most extensive thromboemboli. In cases with a sufficient degree of vascular obstruction to produce hypercapnia, the hemodynamic sequelae ofacute right ventricular failure usually prove fatal. If the patient survives, the low cardiac output syndrome that results from right heart failure increases -c a:
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Hypoxemia Decreased Pa02and increased alveolar-arterial oxygen tension gradient (P[A-a]OJ commonly accompany acute pulmonary embolism. m.21 However, acute pulmonary embolism can occur with normal Pa02or P(Aa)02. iO The Pa02 often remains normal because hyperventilation lowers PAC02, with a resultant increase ofPA02 • Clinical studies have demonstrated a normal Pa02 in up to 26% of patients with angiographically documented thromboembolt." Calculation ofP(A-a)02 provides a more sensitive measurement of the impaired oxygen transfer associated with acute pulmonary embolismoo•22 because the effects of hypocapnia are considered. A number of factors contribute to the severity of arterial hypoxemia that accompanies acute pulmonary embolism. Preexistent cardiopulmonary disease, a common predisposition for pulmonary embolism, frequently produces arterial hypoxemia. When patients without prior cardiopulmonary disease are studied, a direct relationship is demonstrated between the percentage of pulmonary vasculature obstructed and the measured Pa02 . 23 Other factors that may contribute include reflex bronchoconstriction, atelectasis or infarction of lung tissue,24-16 and the presence of a patent foramen ovale. f:7 Mismatching of ventilation and perfusion, intracardiac and/or intrapulmonary shunting of mixed venous blood, and alveolar hypoventilation each may contribute to a reduced Pa02 following pulmonary embolism. Normal lungs match ventilation to blood flow More than 90% of the cardiac output passes through lung units with 0.1 S V/Q S 10.22 Experimental pulmonary embolism redistributes pulmonary blood flo~ producing low and very high V/Q units (Fig 5). In selected patients with more than 50% of the pulmonary vascular bed obstructed by thromboemboli, substantial rightto-left shunting of mixed venous blood occurs." This increased shunt fraction may represent perfusion of unventilated lung units (V/Q=O) due to atelectasis, or it may result from right ventricular failure accompanied by a patent foramen ovale. 27 •29 •30 In either situa1888
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5. Experimental pulmonary emboli change the normal
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matching of ventilation and perfusion. Neither absolute shunt nor dead space ventilation increases. (From reference 22. Reproduced by permission.)
tion, or in the setting of low V/Q units, reduction of mixed venous POI consequent to low cardiac output further decreases the reduced Pa0l by presenting the pulmonary capillary with a lower P02 . 31 In rare circumstances, an increased PaC02 due to massive pulmonary embolism and ventilatory failure contributes to arterial hypoxemia. Hypoxemia results because the rising PAC02 lowers PAO!, thus decreasing the driving pressure for oxygen transport across the lungs. Differentiation of the pathophysiologic mechanism that is responsible for arterial hypoxemia can guide therapeutic interventions. Arterial hypoxemia caused by mismatching of ventilation and perfusion is easily corrected by the administration oflow-8ow oxygen. In contrast, low-flow oxygen does not correct arterial Pulmonary Physiology during Pulmonary Embolism (c.
GI8fIOfY Elliott)
hypoxemia caused by shunting of mixed venous blood 01IQ = 0). Administration of high Bows of gas mixtures with a high inspired oxygen fraction may adequately support patients with high right-to-left shunt fractions. However, in some instances severe atelectasis causes intrapulmonary shunting of mixed venous blood. Continuous positive airway pressure (CPAP) or positive end-expiratory pressure (PEEP) can increase Pa02 by distending airways.29 Paradoxically if increased pulmonary vascular resistance causes right ventricular failure and intracardiac shunting through a patent foramen ovale, the administration of positive airway pressure (CPAP or PEEP) can increase right ventricular afterload and decrease cardiac output, further decreasing Pa02 • In this setting, correction of arterial hypoxemia is best achieved by reducing right ventricular afterload with therapy such as thrombolysis.j" Alveolar hypoventilation (increased PaCOJ rarely contributes substantially to arterial hypoxemia associated with pulmonary embolism, and usually reflects massive embolism accompanied by severe increases of VdNt and the failure of ventilatory muscles to sustain the compensatory marked increases of minute ventilation. In this setting, positive-pressure ventilation and paralysis to decrease CO 2 production may help until the vascular obstruction can be relieved.
resistances to CO transfer do not necessarily represent anatomic structures. Comparison of morphometric measurements of OLeo with physiologic measurements of DLeo reveal wide discrepancies. The OM and 8 Vc are of approximately equal size when measured physiologically, whereas morphometric D M is about 6 times the size of morphometric 9 Vc.33 Physiologic measurements suggest that OM and Vc contribute equally to DLeo, whereas morphometric determinants suggest that Vc is the major determinant of DLeo. Thus, 8 Vc is best considered that part of the DLeo that varies with hemoglobin and inspired oxygen fraction, and D M is best considered the remaining resistance to CO transfer that is not influenced by hemoglobin or inspired oxygen fraction. 34 •3S Few measurements ofDLeo are available following acute pulmonary thromboembolism.P" The DLco is usually decreased. Sharma et al37 reported measurements of Vc for 40 patients who suffered acute pulmonary embolism. These patients had no prior history of cardiopulmonary disease. Comparison of patients who received heparin with those treated with thrombolytic agents showed significantly greater Vc for the lytic therapy group 1 year after the acute pulmonary embolus (Fig 7).
Carbon Monoxide Transfer
Normal ventilatory control depends on the interaction of sensors and respiratory muscles. The sensors include (1) central chemoreceptors, located on the brain-stem surface, which respond to CO 2 and hydrogen ion concentration; (2) peripheral chemoreceptors, located adjacent to the carotid arteries, which respond primarily to decreased arterial Po 2 ; and (3) proprioceptors, located in lung tissue and muscle spindles of diaphragm, intercostal, and abdominal muscle groups, which respond to stretch and irritation. Hyperventilation commonly accompanies acute pulmonary embolism.P The increased minute ventilation usually leads to hypocapnia and respiratory alkalosis, The mechanisms that lead to alveolar hyperventilation following pulmonary embolism are undefined. However, correction of hypoxemia with supplemental oxygen seldom reverses respiratory alkalosis, suggesting that proprioceptors are important contributors to hyperventilation associated with pulmonary emboli. Limited data suggest that irritant and juxtacapillary sensors contribute to the reflex stimulation of ventilation by pulmonary emboli."
The pulmonary diffitsion capacity for carbon monoxide (DLeo) measures the amount of CO transferred from alveolar gas to pulmonary capillary blood per minute for each millimeter of mercury of CO driving pressure. In 1957, Roughton and Forsterw derived a relationship of physiologic factors that influence DLeo. Three factors that affect CO diffusion include (1) the resistance offered by the membranes (DM); (2) the volume of blood in the pulmonary capillaries (Ve), and (3) the volume of CO that each milliliter of blood will take up for each millimeter of mercury of pressure (8). The relation that Roughton and Forster derived for these variables is as follows: lIDLeo = 1/9 Vc + l/DM.
Pulmonary capillary blood volume 01c) is determined by measuring DLeo several times at widely different inspired oxygen concentrations. The differing oxygen concentrations change the number of milliliters of oxygen bound to hemoglobin in pulmonary capillary blood and thus change 8. A plot of the reciprocals of the measured DLeo and 8 pairs allows a line to be fit by least squares. Since the relationship I/DLco = 1/8 Vc + I/DM is a linear equation (y =mx + b), where l/DM = b is the y intercept and 11 Vc = m is the slope, Vc is the reciprocal of the slope plotted from repeated measurements of DLeo at varying inspired oxygen fractions (Fig 6). .An important concept is that these physiologic
VENTILATORY CONTROL
AIRWAY RESISTANCE
The resistance to airflow is an important determinant of the work of breathing. AiJway resistance is critically dependent on lung volume and the radius of the conducting airways. A number of clinical and experimental observations suggest that airway resisCHEST I 101 I 4 I APRIL. 1992 I SUpplement
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tance may increase following pulmonary emboli;39-43 however, direct measurements of airway resistance in humans following well-documented acute pulmonary embolism are not readily available. Clinicians have described wheezing acutely following pulmonary emboli.'" Furthermore, experimental models of acute pulmonary embolism demonstrate that airway con-
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striction occurs adjacent to the embolized lung segment. For example, Thomas et al40 demonstrated that airway resistance increases following embolization of autologous thrombi to dog lungs. Available evidence suggests that serotonin mediates the bronchoconstrtction that accompanies thromboembolism. 39 •40 .
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7. Pulmonary capillary blood volume (Vc) is greater for thrombolytic-treated patients than for heparin-treated (H) patients when measured 2 and 52 weeks after acute pulmonary embolism. (From reference 37. Reproduced by permission.) FIGURE
188S
Pulmonary Physiology during Pulmonary Embolism (C. GI8fIOrY EllIott)
COMPLIANCE
Pulmonary compliance is another important determinant of the work of breathing. The total compliance of lungs is decreased by pulmonary edema, fibrosis, and atelectasis. As is the case with airway resistance, both clinical and experimental observations suggest that the pressure-volume characteristics of lungs are altered by acute pulmonary embolism, but direct measurements of pulmonary compliance following well-documented acute pulmonary embolism are not readily available. 41,a In experimental models of total pulmonary artery occlusion, loss of pulmonary surfactant develops distal to the occlusion. 45 ,46 Atelectasis and edema result. Furthermore, clinicians have described the development of pulmonary edema when acute thromboemboli are lysed. 41 ,48 Such edema presumably results from reperfusion injury to the alveolar capillary bed. Thus, several lines of evidence suggest that acute pulmonary embolism can decrease pulmonary compliance. PULMONARY INFARCTION
Pulmonary infarction (ie, death of lung tissue distal to embolic obstruction) is an uncommon sequela of pulmonary thromboembolism.P'" The lung, unlike other tissues, has 3 sources of oxygen: (1) the pulmonary arteries, (2) the airways, and (3) bronchial arteries arising from the aorta or intercostobronchial trunk. In addition, nutrients may reach lung tissue distal to a pulmonary artery obstruction by retrograde How of oxygenated blood from the pulmonary veins. 52 Clinical and pathologic studies demonstrate that pulmonary infarction accompanies occlusion of small pulmonary arteries. SO,53 In contrast, occlusion or ligation ofcentral pulmonary arteries does not lead to pulmonary infarction because of the bronchial arterial blood supply 53 Dalen et al53 suggested. that pulmonary infarction results when smaller pulmonary arteries are 0bstructed and hemorrhage into the airways persists, In this scenario, the anastomotic channels that exist between distal bronchial arterioles and pulmonary arterioles allow bronchial arterial blood to enter the pulmonary capillary This blood extravasates into the alveolus. If clearance of alveolar blood is delayed for any reason (eg, left ventricular failure), then pulmonary infarction results. Advanced heart failure requiring vasodilator therapy was subsequently strongly associated with the occurrence of pulmonary infarction. 54 REVERSAL OF PULMONARY PATHOPHYSIOLOGY BY
THROMBOLYSIS
Thrombolytic therapy for acute pulmonary embolism can reverse the fundamental derangement of normal pulmonary physiology-obstruction of pulmonary arteries. However, secondary derangements
of pulmonary physiology, such as hypoxemia, are inconsistently affected by thrombolysis and, in some instances, may be adversely altered by reperfusion pulmonary edema. Thrombolysis provides reversal of the physiologic consequences of acute pulmonary embolism more rapidly heparin does. Measurements of pulmonary artery pressure and pulmonary vascular resistance, performed 24 to 72 h after the initiation of 6rst-generation thrombolytic agents (streptokinase, urokinase), demonstrate that small, but sigDmcantly greater, decreases of these parameters accompany thrombolysis. 55 ,56 The increase of PaOz was of marginal significance favoring thrombolysis. Second-generation thrombolytic agents (recombinant tissue plasminogen activator) produce similar hemodynamic effects within hours. 51 Quarititative scores of pulmonary angiograms and perfusion scans provide visual evidence of improved perfusion within 24 h after initiation of thrombolytic therap}T.51,58 In contrast to the rapid initial effect of thrombolytic drugs on pulmonary angiograms and scans, subsequent observations at 2 weeks and again at 1 year after the initiation of therapy demonstrate. no difference in the percentage of resolution of perfusion scans between heparin and thrombolytic drugs. 56 These observations raise the importantquestion ofwhether thrombolysis affects residual pathophysiologic alterations of lung function. Comparisons of patients who were randomly assigned. to treatment with thrombolytic therapy or heparin when acute pulmonary embolism was diagnosed demonstrate that physiologic abnor9nialities persist after heparin therapy Sharma et alsQ reported abnormal increases ofmean pulmonary artery pressure ·and pulmonary vascular resistance during exercise an average of 7 years after treatment ofacute pulmonary embolism. Furthermore, the same authors reported that treatment with urokinase or streptokinase was associated with significantly higher Vc measurements than were found with heparin 6 months after the acute pulmonary embolism."
than
SUMMARY
In summary, acute pulmonary embolism causes major pulmonary physiologic derangements. Understanding these alterations. may guide therapy Increased pulmonary vascular resistance results obstruction of the pulmonary arteries, and may result in acute right ventricular failure, hypotension mid death. This most important pathophysiologic de~e ment may be partially reversed by second-generation thrombolytic agents within hours of their administration. Arterial hypoxemia results from mismatching of ventilation and blood flow or from shunting of mixed venous blood. When hypoxemia is refractory to high inspired oxygen fractions (shunt), differentiation be-
from
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tween intrapulmonary and intracardiac shunting may direct therapy. Intrapulmonary shunt is reversed by CPA~ whereas CPAP may adversely affect intracardiac shunt. Relief of pulmonary artery obstruction by thrombolysis may correct hypoxemia resulting from intracardiac shunts. REFERENCES
1 Harris ~ Heath D. The human pulmonary circulation: its form and function in health and disease, 2nd ed. New York:ChurchillLivingstone, 1977; 22-30, 130 2 Craig RJ, Selzer A. Natural history and prognosis of atrial septal defect. Circulation 1968; 37:805-15 3 Cournand A, Riley RI, Himmelstein A, et al. Pulmonary circulation and alveolar ventilation-perfusion relationships after pneumonectomy. J Thorac Surg 1950; 19:80-116 4 Carlens E, Hanson HE, Nordenstrom B. Temporary unilateral occlusion of the pulmonary artery. J Thone Surg 1951; 22:52736 5 Sharma G, McIntyre KM, Shanna S, et aI. Clinical and hemodynamic correlates in pulmonary embolism. Clin Chest Med 1984; 5:421-28 6 McGoon MD, Van Houtte PM. Aggregating platelets contract isolated canine pulmonary arteries by releasing 5-hydroxytryptamine. J Clio Invest 1984; 74:828-33 7 Thomas D~ Gurewich ~ Ashford TR Platelet adherence to thromboemboli in relation to the pathogenesis and treatment of pulmonary embolism. N Eng) J Med 1966; 274:953-56 8 Huval ~ Mathieson MA, Stemp L], et al, Therapeutic benefits of 5-hydroxytryptamine inhibition foUowing pulmonary embo-lism. Ann Surg 1983; 197:3220-25 9 Huet Y, Brun-Buisson C, Lemaire F, et aI. Cardiopulmonary effects of ketanserin infusion in human pulmonary embolism. Am Rev Respir Dis 1987; 135:114-17 10 Coleridge JC, Kidd C. Electropbysiologic evidence of baroreceptors in the pulmonary artery of the dog. J Physiol 1960; 150:319-31 11 Vesity AM, Bevan KA. Distribution of nerve endings in the pulmonary artery of the cat. Science 1962; 135:785-86 12 Laks MM, Juratsch MS, Garver D, et al, Acute pulmonary artery hypertension produced by distention of the main pulmonary artery in the conscious dog. Cbest 1975; 68:807-13 13 Dantzker DR, Bower JS. Partial reversibility of chronic pulmonary hypertension caused by pulmonary thromboembolic disease. Am Rev Respir Dis 1981; 124:129-31 14 Bouchama A, Curley ~ Al-Dossary S, et aI. Refractory hypercapnia complicating massive pulmonary embolism. Am Rev Respir Dis 1988; 138:466-68 15 Haynes J8, Iseman MD. Massive pulmonary embolism presenting with hypercapnia and minimal intrapulmonary shunting. Rocky Mountain Med J 1979; 77:135-37 16 Riley RL, Permutt S, Said S, et al. Effect of posture on pulmonary dead space in man. J Appl Physioll959; 14:339-44 17 Rea HH, Withy JJ, Seelye ER, et ale The effects of posture on venous admixture and respiratory dead space in health. Am Rev Respir Dis 1977; 115:571-80 18 Baker R, Burld NK. The effects of alterations in ventilatory pattern on the ratio of dead space to tidal volume [abstract]. Chest 1982; 82:243 19 Burld NK. The dead space to tidal volume ratio in the diagnosis of pulmonary embolism. Am Rev Respir Dis 1986; 133:679-85 20 Critanic D, Merino PL. Improved use of arterial blood gas analysis in suspected pulmonary embolism. Chest 1989; 95:4851 21 Hoellerich VL, Wigton RS. Diagnosing pulmonary embolism using clinical findings. Arch Intern Med 1986; 146:1699-1704
1708
22 Dantzker DR, Bower JS. Alterations in gas exchange following pulmonary thromboembolism. Chest 1982; 81:495-501 23 McIntyre KM, Sasahara AA. The hemodynamic response to pulmonary embolism in patients without prior cardiopulmonary disease. Am 1 Cardio11971; 28:288-94 24 Levy SE, Simmons DH. Mechanism of arterial hypoxemia foUowing pulmonary thromboembolism in dogs. J Appl Physiol 1975; 39:41-6 25 Levy SEt Simmons DH. Redistribution of alveolar ventilation foUowing pulmonary thromboembolism in the dog. J Appl Physiol1974; 36:60-8 26 Severinghaus ~ Swanson E~ Finley J, et al. Unilateral bypoventilation produced by occlusion of one pulmonary artery. J Appl Pbysiol 1961; 16:53-60 Herve PH, Petitperez Simonneau G, et al. The mechanisms of abnormal gasexchange in acute massive pulmonary embolism [letter]. Am Rev Respir Dis 1983; 128:1101 28 D'Alonso GE, Bower IS, DeHart et aI. The mechanism of abnormal gas exchange in acute massive pulmonary embolism. Am Rev Respir Dis 1983; 128:170-72 29 D'Alonzo GE, Dantzker DR. The mechanisms of abnormal gas exchange in acute massive pulmonary embolism [letter]. Am Rev Respir Dis 1983; 128:1101-02 30 Shenoy MM, FriedmanSA, Dhar S, et aI. Streptokinase lysis of intraventricular thrombus and pulmonary emboli with resolution of acquired intracardiac shunt. Ann Intern Med 1985; 103:65-6 31 Manier G, Castaing Y, Guenard ,H. Determinants of hypoxemia during the acute phase of pulmonary embolism in bumans. Am Rev Respir Dis 1985; 132:332-38 32 Roughton FJ, Forster BE. Relative importance of diffusion and chemical reaction rates in determining rate of exchange of gases in the human lung, with special reference to true diffusing capacity of pulmonary membrane and volume of blood in the lung capillaries. J Appl Physioll957; 11:290-302 33 Crapo JD, Crapo RO. Comparison of total lung diffusion capacity and the membrane component of diffusion capacity as determined by physiologic and morphometric techniques. Respir Physioll983; 51:183-94 34 Forster RE II. The single-breath carbon monoxide transfer test 25 years on: a reappraisal-I. Physiological considerations [editorial]. Thorax 1983; 38:1 35 Crapo RO, Forster RE. Carbon monoxide diffusing capacity. Clio Chest Med 1989; 10:187-98 36 Bass H. Regional pulmonary function in patients with pulmonary embolism. BuU Physiopathol Respir 1970; 6:123-34 37 Shanna GVKR, Buleson VA, Sasahara AA. Effect oftbrombolytic therapy on pulmonary capillary blood volume in patients with pulmonary embolism. N Eng) J Med 1980;303:842-45 38 KeUey MAt Fishman AI! Pulmonary thromboembolic disease. In: Fishman ~ ed. Pulmonary diseases and disorders. New York: McGraw- Hill, 1988; 1062 39 Comroe JH, Van Lingen B, Stroud RC, et aI. Reftex and direct cardiopulmonary effects of 5-0H-tryptamine (serotonin): their possible role in pulmonary embolism and coronary thrombosis. Am J Physiol 1953; 173:379-86 40 Thomas D~ Stein M, Tonabe G, et aI. Mechanism ofbronchoconstriction produced by thromboemboli in dogs. Am J Physiol 1964; 206:1207-12 41 Gurewich ~ Thomas D~ Stein M, et aI. Broncboconstriction in the presence of pulmonary embolism. Circulation 1963; 27:33945 42 Dunn JS. The effects of multiple embolism of. pulmonary arterioles. Q J Med 1920; 13:129-47 43 Colp CR, WiUiams MH. Pulmonary function following pulmonary embolization. Am Rev Respir Dis 1962; 85:799-807 44 Moser KM. Pulmonary embolism. In: Murray JF, Nadel jA,
en
e
e
Pulmonary Physiology during PumonaIy EmboIsm (C. Gregory EllIott)
45
46
47
48 49 50 51
52
eds. Textbook of respiratory medicine. Philadelphia: WB Saunders, 1988; 1308 Finley TH, Swensen E~ Clements jA, et ale Changes in mechanical properties, appearance and surface activity of extracts of one lung following occlusion of its pulmonary artery in the dog. Physiologist 1960; 3:56-72 Chernick ~ Hodson WA, Greenfield LJ. Effect of chronic pulmonary artery ligation on pulmonary mechanics and surfactant. J Appl Physioll966; 21:1815-19 Ward BJ, Pearse DB. Reperfusion pulmonary edema after thrombolytic therapy of massive pulmonary embolism. Am Rev Respir Dis 1988; 138:1308-11 MartinTR, Sandblom RJ, Johnson RJ. Adult respiratory distress syndrome following thrombolytic therapy for pulmonary embolism. Chest 1983; 83:151-53 Parker BM, Smith JR. Pulmonary embolism and infarction. Am J Med 1958; 24:402-27 Tsao MS, Schraufnagel D, Wong NS. Pathogenesis of pulmonary infarction. Am J Med 1982; 72:599-608 Freiman D, Wessler S, Lertzman W Experimental pulmonary embolism with serum-induced thrombi aged in vivo. Am J Patholl962; 39:95-104 Butler J, KowalskiTF, Willoughly S, et ale Preventing infarctions
53
54 55
56 57
58
59
after pulmonary artery occlusion [abstract]. Clio Res 1989; 37:163A Dalen JE, Heffakee CI, Alpert JS, et al. Pulmonary embolism, pulmonary hemorrhage, and pulmonary infarction. N Engl J Med 1977; 296:1431-35 Schraufnagel DE, Tsao MS, Vas IT, et aI. Factors associated with pulmonary infarction: a discriminant analysis study. Am JClio Patholl985; 84:15-8 Miller GA, Sutton GC, Kerr IH, et aI. Comparison of streptokinase and heparin in treatment of isolated acute massive pulmonary embolism. 8MJ 1971; 2:681-84 Hyers TM, Sasahara AA, Cole CM, et al. The urokinase pulmonary embolism trial. Circulation 1973; 47(suppl II): 4&-59 Goldhaber SZ, Kessler CM, Heit J, et ale Randomized controlled trial of recombinant tissue plasminogen activator versus urokinase in the treatment of acute pulmonary embolism. Lancet 1988; 2:293-98 Goldhaber SZ, Vaughan DE, Markis JE, et ale Acute pulmonary embolism treated with tissue plasminogen activator. Lancet 1986; 2:886-89 Sharma G~ Follend ED, McIntyre KM, et aI. Long-term hemodynamic benefit of thrombolytic therapy in pulmonary embolic disease [abstract]. J Am Coll Cardioll990; 15:65A
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