Pulmonary Embolism and Infarction

Pulmonary Embolism and Infarction H. WILLIAM HARRIS, M.D.*

KNOWLEDGE of the pathogenesis and pathological physiology of many pulmonary diseases has advanced during the past decade. Many reports in this volume, particularly those concerned with pulmonary infection, record significant gains in the prevention, treatment and control of these diseases. However, pulmonary embolism and infarction remains a very common and serious disease, som.etimes impossible to prevent, difficult to diagnose, and fatal in spite of the best treatment available. Even though most practicing physicians diagnose and treat patients with pulmonary emboli, it is not possible to determine accurately the true incidence of the disease. Proof of pulmonary embolism and infarction can be obtained only at autopsy. At the Massachusetts General Hospital, evidence of pulmonary embolisnl was found in 9 per cent of routine autopsies over a ten year period, whereas 14 per cent of a special study group of 400 cases, examined more carefully by Hampton and Castleman, had pulmonary embolism or infarction. 4 The frequency with which the disease is detected at autopsy depends also upon the age of the patients examined. Moran 10 observed pulmonary emboli at autopsy in 23 per cent of the patients dying in a custodial institution, and Towbin 15 discovered postmortem evidence of the disease in 25.7 per cent of 512 patients who died in the Columbus State Hospital. Short14 found pulmonary embolism the most common cause of acute pulmonary disease occurring in a general hospital in England. Revie\\ring the clinical diagnoses at the Graduate Hospital in Philadelphia, Israel and Goldstein 5 found pulmonary embolism to be more frequent than either pneumonia or bronchogenic carcinoma. Not only is this disease being more frequently detected, but also the incidence is increasing, o,ving both to a generally ageing population and to the greater life expectancy of individuals with chronic incurable illnesses which predispose to thrombo-embolic disease.

PATHOLOGY

Pulmonary embolism refers to the passage of any abnormal material in the blood from the systemic veins or the right heart chambers into the

* Chief, Medical Service, Veterans Administration Hospital, Salt Lake City, Utah; Assistant Professor of Medicine, University of Utah College of Medicine. 69

70

H. William Harris

pulmonary artery or its branches, resulting in partial or complete occlusion of the pulmonary vessel. Under certain circumstances foreign materials such as air, fat, amniotic fluid, bone or extraneous objects (bullets) may embolize to the lungs. Hovvever, the most common and clinically the most important foreign material is an intravascular blood clot. The usual sites of venous thrombi which detach and embolize to the lung are: (1) the veins of the lower extremities, (2) the chambers of the right heart, and (3) the pelvic veins. Precise data indicating the frequency of various sites of thrombi ,vhich detach and cause pulmonary embolism are impossible to obtain, for determination of the original site is possible only in autopsied cases. Furthermore, locating the origin of emboli at autopsy may be difficult since: (1) careful dissection of the leg veins is seldom performed in the routine autopsy; (2) all of the thrombus may have detached, leaving the veins free of clot at the time of autopsy; and (3) thrombi may be present in more than one site. The majority of report~ indicate that well over half of fatal pulmonary emboli originate in the leg veins. The events ,vhich may follovv a pulmonary embolus differ in separate individuals, and vary according to the size and location of the embolus, the pre-existing state of the pulmonary and cardiovascular systems, the influence of autonomic reflexes, as ,veIl as to other poorly understood factors. The clinical and pathological sequelae which may result from a pulmonary embolus are often unpredictable. Large clots, however, vvhich occlude the pulmonary artery or both main branches lead to rapid death because of marked reduction of left ventricular cardiac filling and output. An embolus which occludes a major branch of the pulmonary artery or, occasionally, one which terminates in a lobar branch may prove fatal. Death in this instance is usually attributed to acute pulmonary hypertension resulting from reflex pulmonary arterial vasoconstriction. Emboli which occlude a major or peripheral branch of the pulmonary artery may cause symptoms of acute embolism without clinically detectable abnormality of the lung parenchyma supplied by the occluded vessel. The thrombus may then become organized, fibrotic, and recanalization may occur. With repeated attacks the pulmonary arterial circulation may become sufficiently obstructed to cause pulmonary hypertension, right ventricular enlargement, and cardiac decompensation. The changes which occur in lung parenchyma, resulting from the embolic occlusion of a pulmonary artery branch, have been the subject of controversy. Undoubtedly, significant confusion has arisen from the meaning of the term "pulmonary infarct." Clinicians employ this term rather loosely to indicate pulmonary parenchymal consolidation resulting from pulmonary embolism, as detected by clinical methods such as physical examination and chest roentgenogram. Pathologists, on the other hand, use the term more precisely to define a hemorrhagic extravasation into the pulmonary parenchyma associated with necrosis of lung

Pulmonary Embolism and Infarction

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tissue. Experimental evidence indicates that neither pulmonary embolism in animals nor eurgicalligation of pulmonary artery branches in humans produces pulmonary infarction, as defined by the pathologist. However, as stated by Parker and Smith in their excellent review,11 "if the general circulation of the lung has been previously disturbed, embolism invites the onset of insidious necrosis of the parenchyma." Such pulmonary infarcts, associated with lung necrosis, are seen commonly in patients with heart disease, particularly when accompanied by cardiac decompensation, and in other individuals with various chronic diseases of the lungs. In clinical practice it is commonly observed that patients without demonstrable heart or lung disease may, during an attack of thrombophlebitis, develop symptoms characteristic of pulmonary embolism, followed by the symptoms usually associated with pulmonary infarction, namely, pleuritic pain, cough and hemoptysis; and in these cases signs of parenchymal consolidation are readily determined by physical examination and chest roentgenogram. Consistently, the clinician terms this disease process "pulmonary infarction," and the parenchymal infiltrate a "pulmonary infarct," regardless of the presence or absence of lung necrosis. Only rarely, when accompanied by cavitation, can the presence of lung necrosis be detected by clinical methods. Castleman,4 aware of this discrepancy, noted that, in many instances, experimental emboli in animals did produce parenchymal lesions which consisted of "edema, red blood cells, and a few leukocytes in the alveoli," and in addition he observed similar hemorrhagic consolidation in the lungs of humans. According to strict criteria, these lesions cannot be called infarcts; therefore Castleman termed them Hincomplete infarcts." Undoubtedly, an "incomplete infarct" causes the transitory pulmonary infiltrate observed by the clinician in a previously healthy individual who has a pulmonary embolus. This lesion usually resolves without residual parenchymal damage. The true necrotic infarct heals by fibrosis; eventually only a shrunken scar remains at the original site of infarction. Cavitation, due to liquefaction of necrotic tissue and sloughing into a bronchus, rarely develops. However, if bacterial invasion of the infarcted lung occurs either by spread of organisms from an infected embolus or by contamination from the bronchial tree, suppuration and pulmonary abscess may result. Venous Thrombi

Conditions which cause the pooling of blood in the veins predispose to the formation of thrombi. The most common predisposing cause is cardiac decompensation due to heart disease of all types. However, thrombi occur in veins of the lo,ver extremities during the course of many chronic illnesses, particularly those associated with debility and requiring prolonged bed rest. Abdominal or pelvic operations, pregnancy, or trauma and infections of the lower extremities may be complicated by

72

H. William Harris

the development of thrombophlebitis of the leg veins. Thrombi may form \vithin the right atrium or atrial appendage in those diseases which result in enlargement of the right atrium, atrial fibrillation or congestive failure. Any condition which leads to the pooling of blood within these chambers favors the formation of clots. Subendocardial injury of the right ventricle, as occurs in myocardial infarction, may lead to the formation of mural thrombi \vhich may subsequently detach and embolize to the lungs. Thrombosis of the pelvic veins results most often from infections or tumors of the bladder, prostate, rectum, uterus or fallopian tubes. CLINICAL MANIFESTATIONS OF PULMONARY EMBOLISM

The clinical manifestations of pulmonary embolism are markedly varied. Some cases remain entirely without symptoms while others suffer sudden and unexpected death. Certain cases develop only the symptoms of embolism, whereas others may have only the symptoms caused by pulmonary infarction. Most individuals first develop symptoms related to pulmonary embolism, followed by those due to the infarct. In addition, the symptoms, physical signs, and laboratory findings so often cited as being typical of pulmonary embolism and infarction occur frequently in many other acute and chronic diseases of the heart and lungs. The most common symptom of pulmonary embolism, acute unexpected dyspnea, may be mild and of brief duration or severe and persistent. The dyspnea is usually sudden in onset and unrelated to exertion. Often the patient can indicate the exact instant when respiratory distress began. The examining physician may find the patient's complaint of respiratory distress disproportionately more severe than would be expected from the observed degree of hyperventilation. The cause for dyspnea in pulmonary embolism is not entirely understood, but it is commonly considered to result from hypoxia and from autonomic reflexes which stimulate the respiratory center. TVeakness is also a common symptom and probably is due to the reduction of cardiac output resulting from mechanical and reflex blockage of the pulmonary circulation. In some cases chest pain is a prominent symptom. It may vary from a vague sensation of thoracic discomfort to excruciating substernal pain, indistinguishable from that of myocardial infarction. The pain may be caused by reduction of coronary blood flo'\v, due to a lowered arterial blood pressure and cardiac output; or it may result from acute disten tion of the pulmonary artery due to mechanical block of the pulmonary arterial flo\v. Severe anxiety, confusion, convulsions, or coma caused by a reduction of cerebral blood flow may also occur in pulmonary embolism. The patient with an acute pulmonary embolus usually appears pale and anxious, and sweats excessively. Cyanosis may be observed. The heart rate is almost always increased. Paroxysmal tachycardia or arrhythmia, notably atrial fibrillation, may develop, particularly in cases

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73

with pre-existing heart disease. Right ventricular dilatation may be evidenced by abnormally distended veins, an increased intensity of the second pulmonic sound, a pulmonic systolic murmur, and by a diastolic gallop rhythm. Enlargement of the pulmonary arteries, abrupt termination\.of the vascular shadow at the site of the embolic occlusion, and decreased density of the vascular markings have been described 10 as radiologic clues to the presence of pulmonary embolism. However, the chest roentgenogram is usually normal and is only rarely helpful in establishing the diagnosis. A chest x-ray should al,v-ays be obtained, not only to look for these signs, but also to rule out other possible diagnoses. The typical electrocardiographic abnormality results from dilatation and strain of the right ventricle. g Pulmonary embolism is suggested by the presence of a deep S wave in Lead I with a deep Q wave in Lead Ill, depressed S-T segments in Leads I and 11, and inverted T waves in Leads 11 and III and in the precordial leads over the right ventricle. How frequently electrocardiographic abnormalities are observed depends upon the severity of the case and how often tracings are obtained. CLINICAL MANIFESTATIONS OF PULMONARY INFARCTION

In the following discussion the term pulmonary infarct is used to indicate either a transitory parenchymal hemorrhagic lesion (incomplete infarct) or the true infarct with necrosis. The clinical manifestations are not highly specific, for the symptoms and signs seen in pulmonary infarction may occur as well in a wide variety of lung diseases. The most common symptom is pleuritic pain; this occurs more consistently in pulmonary infarction than in any other acute disease involving the lung parenchyma. Since infarcts are al,vays located in the periphery of the lung,4 and one or more surfaces of the pleura are involved, the pleura is often covered by fibrinous exudate and serous fluid. The pleuritic pain may be mild and transitory or severe and persistent. It may first occur while the patient is still experiencing the symptoms of pulmonary embolism, or it may be delayed and occur one or two days after the symptoms of embolism have subsided. Frequently, the abrupt onset of pleuritic pain is the only symptom indicating the presence of pulmonary emboli and infarcts, and for this reason pulmonary infarction must always be considered a possible cause for unexplained pleural pain. Tenderness of the ribs and intercostal spaces may be present in the area of pleural pain. This may also be a prominent symptom in injuries of the chest or in epidemic pleurodynia, but it occurs more often in pulmonary infarction than in most other acute diseases of the lung. Pulmonary infarcts are often located in the inferior portions of the lower lobes, adjacent to the diaphragmatic pleura. In these cases pleural pain and tenderness may be referred to the upper abdomen, and the symptoms and physical signs may be easily mistaken for those of acute intra-

H. W illiam H arris abdominal diseases, particularly cholecystitis or ruptured peptic ulcer. Severe pleuritic pain may cause dyspnea by restriction of motion of the thoracic cage and diaphragms. Cough may be present, but is seldom severe, paroxysmal or distressing. When present, the sputum is usually mucoid, odorless, and rarely contains pus. H emoptysis is usually limited to blood streaks in the sputum, but frank, brisk hemoptysis may occur and may persist for several days. Fever often is present, but seldom exceeds 1020 F. Shaking chills are rarely associated with bland pulmonary infarcts, although a few patients note chilly sensations. Shaking chills may develop in patients with infected emboli or with infected pulmonary infarcts. Jaundice occasionally develops and has been attributed by some observers 6 to the absorption of hemoglobin from the destroyed erythrocytes in the infarct. However, usually the hyperbilirubinemia is predominantly of the direct-reacting type and other confirmatory evidences of liver disease can be found. Physical examination of the lungs may be completely normal if the infarct is small, and if the pleural changes are minimal. When present, the physical signs may result from pleuritis, pleural effusion, or from parenchymal consolidation. There are no specific physical signs by which pulmonary infarction can be differentiated from other pulmonary diseases associated with consolidation of the parenchyma. Leukocytosis is common but, in the uncomplicated infarct, seldom exceeds 15,000 cells per cu. mm. The urine urobilinogen concentration may be increased during the period of resolution of the infarct. The pleural fluid may appear straw-colored or bloody. It has the specific gravity and the protein content of an exudate. Although polymorphonuclear cells may be found in the pleural fluid, the number of erythrocytes present usually exceeds that of the leukocytes. Cultures of the pleural fluid are sterile. Much has been written of the radiological characteristics of pulmonary infarcts. 3 • 4. 7 Although most radiologists agreed that signs of pleural abnormality (elevation of the diaphragm, blunting of the costophrenic angle, the shadow of pleural effusion) are commonly seen in pulmonary infarcts, they do not completely agree as to the usual x-ray appearance of the infarct. Traditionally, the typical x-ray appearance has been thought to be that of a triangle or pyramid, the base of which is directed toward the periphery and the apex toward the hilum of the lung. Hampton and Castleman4 obtained chest x-rays after death on patients suspected of having pulmonary emboli or infarcts, and compared the x-ray findings with the lesions discovered at autopsy. They found that pulmonary infarcts usually present distinctly defined borders by x-ray, but only if views are obtained in several projections. The infarcts demonstrated by x-ray were roughly triangular, with the apex directed toward the periphery of the lung and the base directed toward the hilum. The central border of the infarct usually appeared rounded or "humped." The base of

Pulmonary Embolism and Infarction

75

the infarct never extended to the hilum, and x-rays always demonstrated a clear, uninvolved area of lung parenchyma between the medial border of the infarct and the hilum. Although chest roentgenograms are of great value in detecting pulmonary infarcts and in determining their size, shape and location, the abnormalities which appear on radiological study are not specific. Similar x-ray findings may be obtained in patients with pneumonia, lung abscess, tuberculosis, tumors and other pulmonary diseases. PREVENTION

Since each episode of pulmonary embolism exposes the individual to a mortality risk, and some patients with massive or repeated pulmonary emboli die in spite of treatment, the ultimate control of this disease will require its prevention. For this purpose we need more accurate means of predicting those individuals who will develop venous thrombi, and a method to prevent their formation. The present means for predicting susceptible individuals are crude, for all patients with known predisposing diseases must be suspected as candidates for pulmonary embolism. The currently available methods used to prevent thrombophlebitis are early ambulation, leg exercises, and elastic stockings, used in all patients with predisposing clinical conditions. The value of early ambulation has not been proved, for in some studies the incidence of pulmonary embolism was essentially unchanged. 8 Wilkins and Stanton 16 advocate the use of elastic stockings on the lower extremities in order to increase the rate of flow through the veins by decreasing their caliber. They observed a significant reduction in the occurrence of pulmonary embolism by this means. It is important that the stockings fit snugly and be maintained in the proper position; many patients allow them to wrinkle and to slip downward, thus obstructing rather than augmenting venous blood flow. Surgicalligation of the femoral veins or, less often, of the vena cava, has been widely employed to prevent pulmonary embolism in patients with thrombophlebitis of the leg veins, or to prevent additional emboli in patients with nonfatal pulmonary embolism. At present, anticoagulants (chiefly heparin and Dicumarol) are used more commonly for this purpose. The evidence indicates that either method of treatment is often successful. However, neither mode of therapy can be generally used as prophylactic, since for this purpose every individual with an illness which predisposes to venous thrombi would require treatment. Simply the vast numbers of individuals involved renders this method of prevention impractical. Until better methods for the prevention of venous thrombi are available, the physician must rely on his clinical skill for the prompt detection and rigorous treatment of thrombophlebitis in order to prevent pulmonary embolism. In addition, the incidence of pulmonary embolism is so great in individuals with severe and protracted cardiac decompensation that routine anticoagulation therapy is often used for prophylaxis

H. W illiam H arris

76

before any evidence of thrombophlebitis or pulmonary embolism is found. When fully developed, thrombophlebitis can be easily recognized by the classical signs of pain, heat, redness and calf tenderness. In many instances the patient directs attention to his painful extremity. Evidence of early thrombophlebitis is more subtle, however, and diagnosis may require repeated careful examinations of the legs. Often, very slight calf tenderness or minimal pain on walking constitutes the only symptom. One of the early signs of the disease is an increased size of the leg, detected by measurement of the circumference of the calf area. This technique of early diagnosis requires that calf measurements be obtained routinely on virtually every patient admitted to the hospital, and be repeated frequently during the period of illness. It is surprising how few physicians examine the lower extremities carefully, measure the circumference of the calves, and record a complete description of their findings to be used as a control for future comparison when thrombophlebitis or pulmonary embolism is suspected in the patient. Awareness of the physical signs of incipient thrombophlebitis, and a high index of suspicion toward pulmonary embolism will allow the physician to diagnose tentatively many more patients with these conditions. However, their early clinical manifestations are seldom sufficiently specific to provide absolute assurance of their existence. Thus, the physician must be willing to accept evidence which is only suggestive of thrombophlebitis, or of a small pulmonary embolus or infarct, as an indication for prompt and aggressive therapy for these diseases. The policy of watchful waiting for more convincing proof of thrombophlebitis or of pulmonary embolism exposes the patient to a real hazard of sudden death. TREATMENT

Prompt and adequate supportive measures may be life-saving for the patient with an acute pulmonary embolus. Oxygen should be given to prevent hypoxia, vasopressor drugs such as l-norepinephrine are used to combat shock, and morphine or Demerol is indicated to relieve pain and apprehension. Patients who develop pulmonary emboli during the course of congestive heart failure should be treated appropriately for cardiac decompensation, as should those who develop congestive failure following pulmonary embolism. The arrhythmia which sometimes follows a pulmonary embolus usually subsides spontaneously. In some instances, when the paroxysmal arrhythmia persists, or when the patient is in a precarious clinical condition, a rapidly acting digitalis preparation or quinidine may be required to slow the rate or to convert the rhythm. Il[f ,Except for the supportive measures outlined, little else can be done for the individual with a sudden, massive pulmonary embolus, and unfortunately some patients die in spite of therapy. The control of this disease,

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therefore, requires recognition of the existence of venous thrombi and prompt and vigorous measures to prevent embolism. Similar treatment is indicated for the patient ,vith a nonfatal pulmonary embolus or infarct in order to prevent recurrent embolism. Various anticoagulant regimens have been used effectively for this purpose; usually heparin is given initially and continued until hypoprothrombinemia induced by one of the coumarin drugs reaches the optimum range. The proper duration of anticoagulant therapy must be determined for each patient. For most cases, maintenance of the prothrombin level in the therapeutic range should be continued for several weeks after full ambulation is achieved and all evidence of thrombophlebitis has subsided. In some cases, particularly those with multiple pulmonary emboli, pulmonary hypertension and cor pulmonale, anticoagulants should be given for the remainder of the patient's life. Lifelong therapy is also required for patients with rheumatic heart disease ,vho develop atrial thrombi and have multiple attacks of pulmonary embolism. Although bilateral femoral vein ligation is advocated as the treatment of choice by some,2 anticoagulant therapy is more widely used at present. There are, however, specific indications for surgicalligation of the femoral veins or vena cava: (1) when thrombi in the leg veins continue to cause pulmonary embolism in spite of properly regulated anticoagulant therapy; (2) when anticoagulants are contraindicated by the risk of bleeding, chiefly from lesions of the central nervous system or gastrointestinal tract; (3) when the patient cannot or will not cooperate with prolonged management of the anticoagulant regimen. Surgicalligation of the vena cava in properly selected cases may be life-saving, and should be performed in spite of the troublesome complications of pain, weakness and persistent edema which occur in over one-third of the patients subjected to the operation. 1 PROBLEMS IN DIAGNOSIS AND TREATMENT

The wide variety of clinical manifestations of pulmonary embolism and infarction has been extensively reviewed 3 , 11, 12 and emphasized by Israel and Goldstein,5 who found the typical picture of chest pain to occur in only 20 per cent of patients with franl{ venous thrombi. The symptoms and signs may closely simulate other disease processes involving the lungs, heart, abdominal organs or central nervous system. Differentiating a pulmonary infarct from pneumonia, tuberculous pleural effusion or bronchogenic carcinoma may be very difficult; and many cases of pulmonary embolism closely resemble myocardial infarction, angina pectoris or congestive heart failure. Although known to many clinicians, but not sufficiently stressed in the literature, is the fact that with present day diagnostic methods a significant number of cases of pulmonary embolism or infarction can be suspected but cannot be definitely diagnosed by clinical means. Furthermore, many cases suspected

78

H. W illiam H arris

to be pulmonary embolism or infarcts on the basis of adequate and logical clinical evidence, prove at autopsy to be some other disease. The difficulties in diagnosis should not be minimized, since it is only by recognition of the need that more accurate methods of diagnosis may be sought and discovered. In order to determine the accuracy of diagnosis, and to investigate the factors which obscure the diagnosis, the autopsy records over a ten year period of this 160 bed General Medical and Surgical Veterans Administration Hospital were reviewed. Sixty patients were selected who had pulmonary emboli or infarcts at autopsy, and in whom this disease seemed the sole, or an important contributing, cause of death. In the broad sense, each patient represents a failure of either diagnosis or treatment. Some of the patients were examined during life by the author, and all cases were managed by members of a competent house staff, supervised and directed by qualified internists and surgeons of the full-time and attending staff. This review does not include the much larger group of patients whose disease was diagnosed, treated and cured. 'I'able 1 divides the cases into groups according to the predisposing disease. Whether the patient had symptoms before the terminal episode which, retrospectively and in the author's opinion, were definitely those of pulmonary embolism or infarction, is indicated in the table. In some cases the diagnosis was established before death, as indicated by a definite statement in the record by one or more members of the staff; in other cases the diagnosis was completely unsuspected before the terminal massive pulmonary embolus, or before the autopsy. In others it was clear that the physicians were not certain of the diagnosis; pulmonary embolism and infarction were suspected, as were other possible diseases of the heart or lungs. In general, the other diagnostic possibilities listed seemed appropriate and logical on retrospective review. Most patients with an established diagnosis were treated; however, in the 1948 to 1952 period, fewer patients received therapy than did those given a diagnosis during the last five years of the study. Some patients suspected of having pulmonary emboli or infarcts were treated, whereas others were not. It is evident that the diagnosis was established most often when the patient developed symptoms which were consistent with pulmonary embolism or infarction. The diagnosis was less often established when symptoms were absent or when they were caused by coexisting disease, even when the physical and laboratory findings were in keeping with the diagnosis of pulmonary embolism and infarction. The largest group had advanced rheumatic heart disease, mostly with protracted or recurrent cardiac decompensation and atrial fibrillation. In spite of rather subtle clues, the correct diagnosis was established in three-fifths and strongly suspected in another fifth of the cases. In only three of the 15 patients was the diagnosis unsuspected. Over half of these patients were treated in an attempt to prevent pulmonary emboli. The

43

2 5 1

17

3 0 24

· . 60

17

1 3 1

9 0 3

E,tab· lished

14

1 2 3

3 3 2

Suspected

29

8 0 6

3 9 3

Unsuspected

18

1 4 1

8 1 3

TREATED BY ANTICOAGULANT .3 OR VEIN LIGATION

* Chronic rheumatoid arthritis, cerebrovascular accident, carcinoma of pancreas, bronchiectasis, cervical hematomyelia, insulin coma, polycystic kidney disease.

TOTAL.

8 0 9

7

7

8 12 6

0 2

Other

and/ or Inf:l.rct

Pul. Embolism

9 0 5

NUMBER OF CASES

SYMPTOMS

Rheumatic heart disease ........ . .. .15 .. ...... 12 Surgical, postoperative . . 8 Arteriosclerotic heart disease. Pulmonary emphysema and cor · . 10 pulmonale .. .. 5 None .. . .. , . .. . . · .10 Others*.

PREDISPOSING DISEASE

WITH CARDIAC DECOMPENSATION

DIAGNOSIS OF PULMONARY EMBOLISM AND / OR INFARCT

0-

REVIEW OF 60 AUTOPSy-PROVED CASES OF PULMONARY EMBOLI WITH AND WUHOUT PULMONARY INFARCTS (Pulmonary embolism was b elieved to be either the sole cause of death or an important contributing cause.)

~

~

;:s

"" c·

""'" ~

R.

§

~

~.

~

~

~

Table 1

;:s

c

§"

;p

80

H. lVilliam H arris

diagnosis was established some,vhat less frequently in patients with arteriosclerotic heart disease, although in only one-fourth of the group was it completely unsuspected. It is of interest that ten of the total group of 60 patients had severe pulmonary emphysema and cor pulmonale due to this chronic lung disease. The high incidence of pulmonary embolism in patients ,vith pulmonary emphysema is not generally recognized. Although the incidence noted here may be influenced by the predominance of male patients in a Veterans Administration Hospital, personal observations in a ,videI' selection of cases suggest that patients ,vith severe pulmonary emphysema frequently have pulmonary emboli. Pulmonary embolism is difficult to diagnose in these cases; it was established in one and suspected in only one other of the ten cases. The reason undoubtedly is that the markedly limited pulmonary reserve impairs the ability of these patients to tolerate small emboli. Follo,ving a small pulmonary embolus, they commonly develop severe pulmonary insufficiency and die promptly. 'Clinical deterioration is usually interpreted by the clinician as due to bronchopulmonary infection, an even more common complication in these patients. The diagnosis was firmly established in three patients with chronic thrombophlebitis, recurrent pulmonary emboli, and cor pulmonale. However, death occurred in spite of prolonged anticoagulant therapy and, in one case, vena cava ligation as well. The correct diagnosis was suspected but not established in t,vo cases without known predisposing diseases, and with little or no clinical evidence of thrombophlebitis. Pulmonary embolism was unsuspected in three-fourths of the patients who died following operative measures. Most of them had serious, uncontrolled disease, notably incurable malignancy, and continued on a downhill course following operation; the clinical manifestations, for the most part, were caused by the primary disease and there was no evidence of pulmonary embolism until the terminal episode. Only two patients in the surgical group were convalescent from a successful operation when massive, rapidly fatal embolism occurred. In general, the surgical patients appeared to have more massive and single episodes of emboli, and fe,ver preliminary nonfatal episodes, or evidences of thrombophlebitis to direct attention to the need for treatment. Interestingly, the diagnosis was completely unsuspected in cases of coma due to cerebrovascular disease, uremia, or insulin overdosage. The correct diagnosis was established and treatment instituted in 30 per cent of the entire group. In approximately 20 per cent the correct diagnosis was suspected, and in 50 per cent it was unsuspected. These data are in general agreement with those published by others,11 and indicate a real need for better methods of diagnosis and treatment. The ability of the clinician to diagnose this disease can still be improved by an even higher index of suspicion and more meticulous examinations for

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evidence of thrombophlebitis. But still a significant number of patients with the disease will remain undiagnosed until autopsy. A real advance in the control of pulmonary embolism avvaits the development of a practical and reliable laboratory method for the detection of abnormal vascular clots, and the clinical means for removing thrombi before embolism occurs. ILLUSTRATIVE CASES

Some of the difficulties encountered in correctly diagnosing pulmonary embolism and infarction are indicated by the following cases. CASE I. Diagnosis Unsuspected Because the Clinical Manifestations Were Logically Explained by Coexisting Disease. G.M., a 54 year old man, was admitted to the hospital after 2 days of progressive weakness of the extremities which followed a neck injury sustained in an automobile accident. Examination revealed weakness of all extremities and of the thoracic, abdominal and trunk muscles. Hypoactiva reflexes, bilateral ankle clonus, and Babinski signs were present. The cerebral spinal fluid was normal. On the second hospital day the patient complained of moderate dyspnea, believed due to muscle weakness of the thorax. The heart and lungs were normal on physical examination, as were a chest roentgenogram and an electrocardiogram. The patient developed a low-grade fever between the third and sixth hospital days; however, this was attributed to cystitis since, following the installation of an indwelling catheter, pyuria and bacilluria had occurred. The extremities were examined frequently, and calf tenderness was never present; minimal edema of the dorsum of the feet was noted on the fourth and fifth days. The patient was believed to have an acute traumatic injury of the cervical cord and was given supportive therapy. Muscle strength gradually improved, the reflexes beoame more active, and ankle clonus and Babinski signs disappeared. On the sixth day a cervical myelogram was obtained without difficulty; the column of contrast material appeared normal in the cervical and dorsal regions. Three hours later the patient suddenly became unconscious, developed severe cyanosis and shock, and died within 30 minutes. Logically, it was suspected that the sudden, unexpected death might be causally related to the myelographic study. Autopsy revealed mild edema and punctate hemorrhages into the cervical cord. Pulmonary infarcts were present in the right middle and left lower lobes. These lesions showed central necrosis and were thought to have been present for several days prior to death. Death was due to a large pulmonary embolus, 8 cm. in length, which occluded both the right and left branches of the pulmonary artery.

Comment. Retrospectively, one can detect clinical manifestations occurring before the terminal episode which may have been due to pulmonary embolism and infarction. However, each of these symptoms could have been manifestations of the primary disease, which was known to exist. Moreover, anticoagulant therapy was contraindicated by the hematomyelia, and it is doubtful that vena cava ligation should have been done on the basis of the very slight evidence of pulmonary embolism presented here.

H. William Harris -

82

A

B

Fig. 16 (Case 11). A, Prominence of the pulmonary artery segments is seen but otherwise the findings are normal. B, The x-ray shows increased prominence of the pulmonary artery shortly before death from pulmonary embolism. CASE 11. Clinical Manifestations of Multiple -Pulmonary Emboli Resembling Another Disease. S.S., a 56 year old man, noted progressive weight loss, nervousness, palpitation and exertional dyspnea for 6 months before hospital admission. Physical examination revealed slight enlargement of the thyroid and a fine tremor of the extended fingers. Moderate pulmonary emphysema was evidenced by an increased anteroposterior diameter of the thorax and prolonged expiration. The pulse rate was constantly elevated between 100 and 125 beats per minute. Two basal metabolism determinations were plus 44 and plus 47. The serum proteinbound iodine was within the normal range. A diagnosis of thyrotoxicosis was suspected, and treatment with propylthiouracil instituted. There was moderate improvement in the subjective symptoms, but tachycardia persisted and no weight gain occurred. The patient was discharged and continued on treatment; after 10 weeks, however, he was readmitted with recurrence of more severe but similar symptoms. Physical examination was unchanged except that the liver edge was palpable 6 cm. below the costal margin. The basal metabolic rate remained elevated; circulation time and venous pressure determinations were normal. A chest roentgenogram (Fig. 16, .{1) showed prominence of the pulmonary artery segments but was otherwise normal. The electrocardiogram was normal and had not changed since the first hospital admission. The vital capacity was 1.8 liters. The patient was treated with bed rest, increased doses of propylthiouracil, and phenobarbital. However, soon after admission he developed marked weakness, confusion, dyspnea, fever to 1030 F., and rapid atrial fibrillation. He was thought to have an acute thyrotoxic crisis and was treated vigorously with sedation, oxygen, digitalization and cortisone. The acute symptoms gradually subsided, but after 2 days he developed an unproductive cough and rales were detected in the left lower lobe. The blood leukocyte count was 36,000, with 95 per cent polymorphonuclear cells, and a sputum culture yielded predominantly H. influenzae. Streptomycin was given and within 2 days the fever, cough and tachycardia subsided and the abnormal pulmonary findings disappeared. Moderate dyspnea and

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weakness persisted. He continued to improve until 5 days later, when recurrence of fever, atrial fibrillation, and weakness was noted. Although there were no pulmonary symptoms or signs, slight tenderness of the right calf first appeared. Heparin was administered, and the calf tenderness subsided within 24 hours. Anticoagulant ther~py was continued for 14 days and then omitted. Twenty-four hours later the patient developed stupor, weakness, fever, dyspnea and hypotension. A chest x-ray revealed increased prominence of the pulmonary artery branches (Fig. 16, B), and an electrocardiogram revealed right ventricular strain pattern. Vigorous supportive measures were given and anticoagulant therapy reinstituted, but his condition rapidly deteriorated and he died within 48 hours. Autopsy revealed both recent and older organized thrombi widely distributed throughout many of the smaller branches of the pulmonary arteries. There were no pulmonary infarcts. The right ventricle was moderately hypertrophied and dilated. The immediate cause of death was a large laminated embolus which completely occluded the right main pulmonary artery and the arterial branch to the left upper lobe. The thyroid gland was enlarged and revealed some areas of acinar cell hyperplasia. It was impossible to determine whether these represented the changes of hyperthyroidism or were due to treatment.

Comment. Undoubtedly this patient had had recurrent showers of small pulmonary emboli for at least 6 months before death. However, the predominance of systemic symptoms and absence of any clinical evidence of thrombophlebitis or of pulmonary infraction until late in the course of the disease resulted in failure to establish the diagnosis. CASE Ill. D·iagnosis Not Established Because of Statistical Improbability of the Disease. N.S., a 25 year old male student, was in excellent health until 1 month prior to hospital admission, when he noted slight unproductive cough and mild exertional dyspnea. Three days before entry, these symptoms suddenly increased and he was treated with penicillin by his family physician. Two days later he coughed up small quantities of blood-streaked mucus and was noted to be slightly cyanotic. The patient was moderately obese and acutely ill, with dyspnea and slight cyanosis, on admission. The oral temperature ranged between 990 and 1020 F., the pulse rate was 125, and the respiratory rate 30 per minute. He had severe paroxysms of cough followed by marked dyspnea. Signs of consolidation were present over the right upper lobe and at the left lung base. Examination of the heart revealed an intensified second pulmonic sound and a pronounced diastolic gallop rhythm. The extremities were entirely normal. The leukocyte count was 14,700 with 69 per cent polymorphonuclear cells. The electrocardiogram revealed right axis deviation and inverted T waves in Leads 11, Ill, AVF, and in all precordial Leads, VI through V6 • A chest roentgenogram (Fig. 17) revealed a poorly circumscribed area of infiltration in the right upper lobe and small, nondiscrete infiltrates throughout the left lung. The patient was examined by several staff physicians, including the author, shortly after admission. Two chief diagnostic possibilities were considered: (1) severe virus pneumonia with myocarditis, and (2) multiple pulmonary emboli and infarcts. Although the clinical manifestations were quite characteristic of pulmonary infarction, the age of the patient, the lack of predisposing disease, and the absence of signs of thrombophlebitis weighed. heavily against the diagnosis. He was treated by oxygen administration and tetracycline, and showed definite clinical improvement within 12 hours. Fever and gallop rhythm persi3ted, but cough, dyspnea and tachycardia had subsided. Anticoagulant therapy was

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Fig. 17 (Case Ill). A poorly circumscribed area of infiltration is seen in the right upper lobe, and small nondiscrete infiltrates are present throughout the left lung.

reconsidered, but for the reasons stated and because of definite clinical improvement, it was withheld. Twenty-four hours after admission, improvement was sufficient to allow discontinuance of, oxygen. Neither dyspnea nor cyanosis recurred. Thirty-six hours after entry, the patient was almost symptom-free, when he suddenly lost consciousness, had a generalized seizure, and died. A large area of hemorrhagic consolidation without necrosis was found in the right upper lobe on autopsy, and a large embolus occluded the main artery to this lobe. Small incomplete infarcts were found throughout the left lung. The cause of death was determined to be a large embolus, 1 cm. in diameter, which extended from the chamber of the, right ventricle through the pulmonic valve and into the pulmonary artery. Both right and left branches of the pulmonary artery were occluded (Fig. 18). The original site of the thrombus was not discovered, but, in view of its length and diameter, it was suspected to have originated in the leg veins.

Comment. The clinical manifestations in this case were typical of pulmonary infarction. However, the fact that the patient was a previously healthy young man with no evident cause for venous thrombi impressed the clinicians; furthermore, a sense of security was provided by the marked clinical improvement during the first 36 hours. That anticoagulant therapy would have prevented the terminal massive embolism is doubtful. A decision to ligate the vena cava of a previously healthy young individual, seemingly recovering from an acute pulmonary illness, possibly due to pulmonary emboli, would have been made with difficulty.

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Fig. 18 (Case Ill). Gross pathology (see text).

I

CASE IV. Characteristic Clinical Manifestations of Pulmonary Infarction M isdiagnosed. R.M., a 31 year old woman, was admitted with a severe attack of hemolytic anemia. She had had two previous similar illnesses during the past. 6 years. After intensive medical therapy and a stormy, complicated clinical course, she improved sufficiently to have a splenectomy. Transfusions were required postoperatively, and high doses of cortisone were continued. Except for persistent and unexplained melena, the postoperative course was uneventful until the nineteenth day, when there was a sudden onset of severe pleuritic pain in the right anterior chest, accompanied by fever and tachycardia. Physical examination revealed marked tenderness of the anterior and lateral thorax on the right and diminished breath sounds, rales, and a pleural friction rub. Both calves were markedly tender. Chest x-ray (Fig. 19) revealed a wedge-shaped consolidation of the inferior portion of the right lung, and a rounded density with central radiolucency in the superior segment of the left lower lobe. The diagnosis of pulmonary embolism and infarction seemed assured by the typical clinical and radiographic manifestations. Anticoagulant therapy was withheld because of the unexplained melena. Femoral vein ligation was planned, but the patient developed severe abdominal distention, increased fever and shock, and died. Autopsy revealed the perforation of an acute gastric ulcer, and disseminated lesions due to Candida albicans. The left lung contained an abscess, and the right middle and lower lobes revealed heavily consolidated pneumonia due to Candida albicans. There was no evidence of· venous thrombi, pulmonary emboli or infarcts.

Comment. The clinical manifestations in this patient were characteristic of pulmonary infarction and, had the patient survived for a sufficient time, treatment for this disease would have been instituted. However, these manifestations were caused by pulmonary infection.

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Fig. 19 (Case IV). Roentgenogram revealing a wedge-shaped consolidation of the inferior portion of the right lung, and a rounded density with central radiolucency in the superior segment of the left lower lobe.

SUMMARY Pulmonary embolism and infarction are a common and often a serious disease. The diagnosis is easily established in cases with typical clini~al manifestations, and treatment is usually effective in these cases. The correct diagnosis can be strongly suspected but rarely proved during life in cases with few or atypical clinical manifestations. The absence of symptoms or signs, or predominance of clinical manifestations of the primary predisposing disease obscures clinical detection of venous thrombi and pulmonary emboli in a significant number of cases. Awareness of the varied clinical manifestations of pulmonary embolism, and frequent careful examinations of the legs of patients with illnesses which predispose to thrombophlebitis will allow the physician to detect and successfully treat more patients with this disease. Predictably successful prevention of pulmonary embolism, however, requires some objective method, as yet unavailable, for the accurate detection and easy removal of intravascular blood clots.

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22: 359-361 (March) 1956. 2. Byrne, J. J.: Phlebitis. A Study of 748 Cases at the Boston City Hospital. New England J. Med. 253: 579-586 (Oct. 6) 1955. , 3. Chapman, J. S.: Pulmonary Infarction. South. M. J. 45: 597-602 (July) 1952. 4. Hampton, A. O. and Castleman, B.: Correlation of the Postmortem Chest Teleroentgenograms with Autopsy Findings, with Special Reference to Pulmonary Embolism and Infarction. Am. J. Roentgenol. 43: 305-326 (March) 1940.

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5. Israel, H. L. and Goldstein, F.: The Varied Clinical Manifestations of Pulmonary Embolism. Ann. Int. Med. 4-7: 202-226 (Aug.) 1957. 6. Kugel, M. A. and Lichtman, S. S.: Factors Causing Clinical Jaundice in Heart Disease. Arch. Int. Med. 52: 16-29 (July) 1933. 7. Macleod, J. G. and Grant, 1. W. B.: A Clinical, Radiographic and Pathological Study of Pulmonary Embolism. Thorax 9: 71-83 (March) 1954. 8. McCann, J. C.: Thromboembolism. A Comparison of the Effect of Early Postoperative Ambulation and Dicumarol on Its Incidence. New England J. Med. 24-2: 203-207 (F(~b. 9) 1950. 9. McGinn, S. and White, P. D.: Acute Cor Pulmonale Resulting from Pulmonary Embolism; Its Clinical Recognition. J.A.l\f.A. 104-: 1473-1480 (April 27) 1935. , 10. Moran, T. J.: Pulmonary Embolism in Non-surgical Patients with Prostatic Thrombosis. Am. J. Clin. Path. 17: 205-208 (March) 1947. 11. Parker, B. M. and Smith, J. R.: Pulmonary Embolism and Infarction. A Review of the Physiological Consequences of Pulmonary Arterial Obstruction. Am. J. Med. 24-: 402-427 (March) 1958. 12. Sagall, E. L., Bornstein, J. and Wolff, L.: Clinical Syndrome in Patients with Pulmonary Embolism. Arch. Int. Med. 76: 234-238 (Oct.) 1945. 13. Shapiro, R. and Rigler, L. G.: Pulmonary Embolism Without Infarction. Am. J. Roentgenol. 60: 460-465 (Oct.) 1948. 14. Short, D. S.: A Survey of Pulmonary Embolism in a General Hospital. Brit. M. J. 1: 790-796 (Apr. 12) 1952. 15. Towbin, A.: Pulmonary Embolism; Incidence and Significance. J.A.M.A. 156: 209-215 (Sept. 18) 1954. 16. Wilkins, R. W. and Stanton, J. R.: Elastic Stockings in the Prevention of Pulmonary Embolism. 11. A Progress Report. New England J. Med. 248: 1087-1090 (June 25) 1953.