The Pulmonary Vascular Lesions of the - NCBI

The Pulmonary Vascular Lesions of theAdult Respiratory Distress Syndrome

JOSEPH F. TOMASHEFSKI, Jr., MD,PAUL DAVIES, PhD, CAROLINE BOGGIS, MD,

REGINALD GREENE, MD,WARREN M. ZAPOL, MD, and

LYNNE M. REID, MD

Specimen arteriography, morphometry, and light andelectron microscopy were used for examination of thepulmonary vasculature of 22 patients who died with theadult respiratory distress syndrome (ARDS), for thepurpose of defining the lesions that contribute to pul-monary hypertension in this setting. The differentlesions correlated with the duration rather than thecause of ARDS. Thromboemboli occurred in 21 pa-tients, and macrothrombi found at autopsy correlatedwith the number of filling defects on antemortem an-giography. Acute endothelial injury was documented

PULMONARY vascular injury is a central feature ofthe adult respiratory distress syndrome (ARDS), andpulmonary hypertension due to an increased pul-monary vascular resistance is virtually always pres-ent.' Recent advances in mechanical ventilation andintensive care of the critically ill have extended thelife span of patients with severe acute respiratoryfailure to several weeks' duration.2 Early in ARDSpulmonary vasoconstriction, thromboembolism, andinterstitial edema, features that are potentially re-versible, can raise the pulmonary artery pressure, butafter several weeks more serious structural changessuch as obliteration of the microcirculation and in-creased arterial muscularization also contribute topulmonary hypertension.38 Pulmonary vascularobliteration and muscularization were recently an-alyzed morphometrically in an autopsy series of 11ARDS patients.7 Otherwise, little quantitative infor-mation is available on the range of pathologic altera-tions in arteries, veins, and lymphatics found in pa-tients dying from ARDS of varying duration. Thechronic arterial changes, particularly, have receivedlittle emphasis.The present report describes an analysis of the pul-

monary vascular findings in 22 patients (including 11

From the Department of Pathology, Children's Hospital MedicalCenter, and the Departments of Anesthesia and Radiology,Massachusetts General Hospital, Boston, Massachusetts

ultrastructurally even in intermediate and late-stagepatients. Fibrocellular intimal obliteration of arteries,veins, and lymphatics and infective vasculitis wereprominent in those surviving beyond 10 days. In long-term survivors, tortuous arteries and irregularly dilatedcapillaries were striking features. Peripheral extensionof vascular smooth muscle and a significant increase inthe percentage of medial thickness of muscular arterieswith duration of ARDS were noted. The pathogenesisand clinical significance of these lesions is discussed.(Am J Pathol 1983, 112:112-126)

described by Snow et al7), using postmortem arterio-graphy, vascular morphometry, and light and elec-tron microscopy. It extends that report to describefully the histologic features and postmortem arterio-graphic appearance of all of the vascular lesions andcorrelates these in each patient with clinical and labo-ratory measurements, the course of the acute lungdisease, and its cause.

Supported by NHLBI SCOR Grant 23591 and in part byGrant RR-01032 from the General Clinical Research Cen-ters Program of the Division of Research Resources, Na-tional Institutes of Health. Data organization and analysiswas performed on the PROPHET system, a national com-puter resource sponsored by the Division of Research Re-sources, National Institutes of Health.

Presented at the American Thoracic Society meeting inLos Angeles, California, May 16, 1982.Accepted for publication March 4, 1983.Address reprint requests to Lynne M. Reid, MD, Depart-

ment of Pathology, Children's Hospital Medical Center,300 Longwood Avenue, Boston MA 02115.Address correspondence to Joseph F. Tomashefski, Jr.,

MD, Department of Pathology, Cleveland MetropolitanGeneral Hospital, 3395 Scranton Road, Cleveland, OH44109.

0002-9440/83/0707-0112$01.55 i American Association of Pathologists

112

VASCULAR LESIONS OF ARDS 113

Materials and Methods Methods

Patient Data

In this series there were 22 patients, 11 men and 11women, ranging in age from 16 to 76 years (median,31 years). The initial causes of ARDS were sepsis (5patients), trauma (4), virus or mycoplasma pneu-monia (6), aspiration of stomach contents (4), bac-terial pneumonia (2), and toxic inhalation (1). ARDSwas diagnosed by the sudden onset of dyspnea withbilateral diffuse infiltrates in the chest radiograph andhypoxemia (Pao2 <50 mm Hg at an FIO2 of 0.5). Allpatients had an endotracheal tube in place and weretreated with supplemental oxygen (FIO2 >0.5) andmechanically ventilated with positive end expiratorypressure between 5 and 20 cm H20 in the respiratoryintensive care unit of the Massachusetts GeneralHospital. The mean pulmonary artery pressure(PAP) was measured at end expiration with a Swan-Ganz catheter using a Statham P27DB transducerand a Hewlett Packard recorder. Zero pressure wastaken as atmospheric pressure in the mid axillaryline. Thirteen patients developed disseminated intra-vascular coagulation (DIC) as diagnosed by fivescreening tests: prothrombin time (>14 seconds), par-tial thromboplastin time (>37 seconds), plateletcount (<150,000/cu mm), fibrinogen concentration(<0.16 g/dl), and concentration of fibrin degradationproducts (FDP) (>1:4). The diagnosis was madewhen in addition to an elevated FDP, three of theother four tests were positive. Bedside balloon occlu-sion pulmonary angiography was performed in 16patients.9 The mean interval between angiographyand death was 9.9 ± 7.1 days.

Retrospectively, each patient was allocated to oneof three groups according to the interval between in-tubation and death. In the early group (interval lessthan 9 days-3 days was the earliest in the series)there were five patients with a mean preterminal PAPof 35 ± 7.3 mm Hg. The eight patients in the inter-mediate group (10-19 days) had a mean PAP of 42.4+ 9.4 mm Hg, and the 9 patients of the late group(20 and more days) had a PAP of 42 ± 3.8 mm Hg.The age range, sex distribution, and causes of ARDSwere similar in each group. Four patients also had ahistory of chronic obstructive lung disease, and twohad pulmonary carcinoma. There were eight patientswith other nonpulmonary diseases, which includedcirrhosis (2 patients), carcinoma (2), blood dyscrasia(2), collagen vascular disease (1), and diabetes (1).These were distributed through all duration groups.In all patients, respiratory failure was either themajor or a significant contributory cause of death.

The right lung of 16 patients and left of 6 were ob-tained at autopsy. In 3 patients only the lower lobewas available for study; in the others, the whole lung.The pulmonary arteries were injected for 4-7 minuteswith a barium sulfate gelatin mixture at 60 C and 74mm Hg pressure. This casting method fills vesselsdown to about those 15 pi in diameter without fillingthe capillaries.The lung was then distended by bronchial instilla-

tion of 1007o neutral buffered formalin at 30 cm H20pressure. After fixation for 1 week, radiographs weretaken of the whole lung and then of each of the 1-cmslices into which the specimen was cut. We tookarteriograms on Kodak X-Omat TL film, using, forintact lungs, an exposure of 70 kv for 0.8 minutes at2.25 mA and, for the lung slices, 45 kv for 0.3minutes. The areal density of injected arteries greaterthan 1 mm in internal lumen diameter (ID) was deter-mined by macroscopic point counting. From eachlung 15-25 blocks were selected by stratified randomsampling10 for microscopic sections (2 x 1 cm). Ad-ditional sections were taken from any lesion whosetype was not included in the random sample.

Tissue was embedded in paraffin, and 4-,.-thicksections were cut and stained with hematoxylin andeosin (H&E) and Miller's elastic van Gieson (EVG)stains. Each slide was examined, and the findingswere related to their appearance on the postmortemarteriogram. For detailed morphometric analysis,three or more of the sections from each pulmonarylobe were arbitrarily selected to represent widelyseparated regions.With an eyepiece reticle, the external diameter

(ED) and medial thickness (MT) of pulmonary ar-teries were measured across their smallest diameter.External diameter was measured to the external elas-tic lamina; MT was expressed as 2 MT x 100/ED,where MT is the distance between internal and ex-ternal elastic laminas. The structure of the pulmo-nary artery, whether muscular, partially muscular, ornonmuscular, was noted for each vessel, and thestructure of the accompanying airway was also re-corded. About 25 arteries were measured per slide.We followed the convention of starting from thelower left corner and measuring all filled arteriesgreater than 20 pi encountered as the slide wasscanned from left to right.Pulmonary artery concentrations were determined

by counting all acinar arteries greater than 20 p indiameter within a given field size (1.65 sq mm). Weassessed 10 such fields per slide, using the same slides,

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114 TOMASHEFSKI ET AL

but not necessarily the same fields, as for vascularwall measurements. Areas of lung necrosis or nonfill-ing were not used for morphometric analysis. Themean concentration of acinar arteries was expressedas arteries per square millimeter. We analyzed thestatistical differences in both arterial concentrationand wall thickness between the three patient groupsusing analysis of variance followed by the Newman-Keuls test for multiple comparisons.11Thromboembolic vascular disease was analyzed

semiquantitatively. Thrombi in arteries with IDsgreater than 1 mm (macrothrombi) were analyzed bydirect inspection of all the lung slices. For each lungslice, all clots that occupied more than 10Gb of thecross-sectional area of arteries with an ID greaterthan 1 mm were counted. A proportion of these clotswere directly sampled for microscopic examination,and the estimate of macrothrombi was determined bymultiplication of the number of grossly observedclots by the percentage of thrombi identified histo-logically. Each lung was scored for macrothrombifrom 0 to + + + as follows: 0, no macrothrombi; +,1-5 macrothrombi; + +, 5-10 macrothrombi;+ + +, >10 macrothrombi. Two of the three singlelobes obtained for study had more than 10 macro-thrombi and were scored as + + +. The other singlelobe had between 5 and 10 macrothrombi; and, if oneassumed that the upper lobe had a similar concentra-tion of thrombi, the figure was doubled and the pa-tient given a score of + + +. To gauge the extent ofthrombosis in arteries with IDs less than 1 mm(microthrombi) for each lung, the percentage of allrandomly selected blocks containing at least 1 micro-thrombus was determined. Lungs were scored from 0to + + + as follows: 0, no microthrombi; +, throm-bi in 0-25% of the slides; + +, thrombi in 25-50%of the slides; + + +, thrombi in >50% of the slides.The angiograms performed antemortem were scoredblindly by two radiologists in consultation as having0, 1, or many pulmonary arterial filling defects.

Finally, tissue for electron-microscopic study wasobtained from 6 patients: 4 patients at open lungbiopsy, 1 at open biopsy and autopsy, and 1 only atautopsy. Autopsy tissue was obtained within 1 hourof death. The tissue was cut into 1-cu mm fragments,fixed in 2.5% gluteraldehyde for 1-2 hours, washedin 1 M cacodylate buffer, and embedded in Polybed812 (Polysciences, Warrington, Pa). Sections werecut at 600-800k, stained en bloc with 5% uranylacetate in buffer and, after sectioning, with 1 07ouranyl acetate methanol; they were examined with aPhilips 300 electron microscope.

Results

General Features

The lungs of patients in the early group wereheavy, airless, and diffusely dark red-blue. Micro-scopically they were characterized by interstitialedema, intraalveolar hemorrhage, hyaline mem-branes, and condensed fibrin in both alveoli andbronchioli. In the intermediate group the lungs weremore densely consolidated with patchy red-brownand yellow-gray areas. Histologically, there wasproliferation of epithelial cells and exuberant orga-nizing granulation tissue. The latter was prominent inalveolar ducts, in some instances obliterating theirlumen. Grossly, the lungs of the late group weresimilar to those of the intermediate group but, inaddition, contained zones of fine cysts in which airspaces were larger, ranging up to 1 mm in diameter,with walls somewhat thicker than normal. Histo-logically, mature fibrous tissue was associated withdistortion and obliteration of alveolar and bron-

Figure 1 -Postmortem arteriogram showing multiple arterial fillingdefects due to organizing and recanalized thromboemboli, withreduced filling of peripheral vessels (36 days after aspiration). (x 2.6)

AJP * July 1983


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Figure 2-Microthrombosis. A-Postmortem arteriogram of normal adult lung. The pleural surface is at the bottom. (x 2.4) B-Arterio-gram of a patient with early ARDS (6 days after aspiration). There are reduced filling of small arteries and prominent, edematous interlobularsepta. (x 2.4) C-Organizing microthrombus adherent to the wall of an alveolar duct artery (17 days after inhalation of toxic fumes). (H&E,x 100) D- Platelet fibrin thrombus (arrow) obstructing the flow of contrast medium in an alveolar wall artery. A hyaline membrane is belowand extravasated red blood cells to the right of the thrombosed vessel (same patient as in B). (H&E, x 250) The arteriograms of tissueblocks illustrated in Figures 2, 10, 13, and 14 were taken under the same X-ray exposure.

chiolar spaces. The three patient groups roughly cor-responded, respectively, to the exudative, prolifera-tive, and fibrotic stages of diffuse lung injury.12-14

Thromboembolic Vascular Disease

Thromboemboli, macroscopically or microscop-ically identified, were the most consistently observedvascular feature, present in 21 of 22 patients. In thearteriograms, they were present as intravascular fill-ing defects with distal nonfilling. Intravascular linearstreaks were due to contrast medium in the recana-lized lumens of thrombi (Figure 1).Macrothrombi were present in 19 patients-(86.4%o)

and were less frequent in those with a prolongedcourse (Figure 3). Microthrombi, also present in 19patients (of these, 2 did not have macrothrombi)were of two types (Figure 2). The first type, found incapillaries and small alveolar wall arteries, was adense, hyaline clot formed of platelets and fibrin.These were numerous in only 3 patients, all in the

early group. The second type of microthrombus wasfound in small preacinar and large intraacinar ar-teries and often included red and white cells andlayered fibrin in addition to hyaline regions. This wasthe more common type, found in all patient groupsas well as in the 3 patients with capillary thrombi(Figure 3). In the postmortem arteriogram, the pres-ence of microthrombi was reflected in reduced fillingof small arteries (Figure 2).The macrothrombus score was highest in patients

with multiple pulmonary arterial filling defects onballoon occlusion pulmonary angiography and low inthose without these defects (Figure 4). Most patientswith filling defects on antemortem angiography hadmicrothrombi, but the number of thrombi variedfrom patient to patient (Figure 4). The group of 13patients with a clinical diagnosis of DIC had no dis-tinctive pattern of thrombosis. Eight of these hadnumerous ( + + - + + + ) and five had sparse (+)microthrombi.

In 2 of the 3 patients with numerous capillary

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Postmortem arteriograms showed a reduction inthe density of filled small arteries in both the earlygroup and the later groups. In patients of the earlygroup this was due to thrombosis or hemorrhage andedema, which apparently compressed alveolar capil-laries. In 7 patients of the intermediate and lategroups, necrotizing vasculitis was focal in 5 and in 2had produced a severe reduction of pulmonary vas-cular cross-sectional area (Figure 5). In each in-stance, vasculitis occurred in areas of necrotizingsuperinfection with bacteria (3 patients), viruses (3),or fungi (1).

Ultrastructurally there was evidence of acute en-dothelial injury in all the lung specimens we ex-amined. Swollen endothelial cells with rarefied cyto-plasm and dilated endoplasmic reticulum encroachedupon the lumens of capillaries (Figure 6). Injured en-dothelial cells were often adjacent to normal-appear-ing cells. Swollen mitochondria containing mem-brane-bound vesicles, and occasional cytoplasmicmyelin figures provided additional evidence of acuteinjury. Some endothelial cells were focally separatedfrom the capillary basement membrane (Figure 7),Late

Figure 3-Number of pulmonary thromboemboli found at autopsy re-lated to the duration of ARDS. Lungs were scored semiquantitativelyfor macrothrombi (upper) and microthrombi (lower). Each point is thescore for a single patient.

platelet fibrin thrombi was the diagnosis of DICmade on the screening tests, but neither of the 2 pa-

tients with a microthrombus score of 0 had a positivescreen for DIC. Macrothrombi were present in vari-able numbers in 11 and absent in 2 patients with clini-cal evidence of DIC.

Infarcts were present in the lungs of 5 patients inthe intermediate group and 1 in the late group. Twopatients had regions of acellular coagulative necrosisnot associated with obstruction of large arteries: in 1

patient from the intermediate group the lung was

diffusely necrotic, and in another, from the lategroup, a 1-cm-deep necrotic band was present sub-pleurally and posterolaterally. Bone-marrow emboliwere prominent in a trauma victim of the earlygroup; whereas refractile, fiber emboli were sparse in1 late-stage patient. For only 1 patient was an extra-pulmonic source of emboli reported at autopsy, al-though in none of the others was mention made ofany special search. In 2 other patients systemic sitesof thrombosis had been identified clinically by eithervenography or radioisotopically labeled fibrinogen.

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and in 2 patients necrotic cells had sloughed into thecapillary lumen. In nonnecrotic cells, both pinocytot-ic vesicles and endothelial tight junctions appearednormal. Intraluminally, platelets were infrequentlyobserved, but leukocytes were seen in 3 patients (2 in-termediate, 1 late), and obstructed numerous capil-laries in the 1 patient whose ARDS followed toxic in-halation. Intracapillary fibrin was noted in 4 patients(2 intermediate, 2 late) and was interposed betweensloughed endothelial cells and the basement mem-brane in 1 from the intermediate group (Figure 7).

In most specimens, capillaries were sparse anddifficult to find by electron-microscopic examination.Chronic changes identified ultrastructurally includedthickened and reduplicated capillary basement mem-branes (Figure 8) and hypertrophic endothelial cellswith prominent filopodia. In 1 patient in the inter-mediate group, markedly tortuous capillaries werepresent against a background of dense, acellular con-nective tissue (Figure 9). Occasionally, structurallynormal pericytes were observed.

In most patients in the intermediate and lategroups, many small arteries and intraacinar veins,viewed by light microscopy, were focally obstructedby eccentric or concentric intimal fibrous tissue vary-ing in degree of cellularity (Figure 10). Intimalvenous sclerosis was focally distributed and histo-logically often appeared as sparsely cellular, looseconnective tissue arranged in an onionskin pattern(Figure 1 1). Other veins, particularly in the lategroup of patients over 40 years of age, had densehyalinized intimal plaques that stained red with


EVG, suggesting collagen. At all stages of the dis-ease, venous thrombi were rare and seen only adja-cent to areas of necrosis. Unfortunately, these largerarteries and veins were not represented in the tissuestudied electron-microscopically.The pulmonary lymphatics also showed structural

alterations. In all patients, dilated lymphatic chan-nels were prominent. Additionally, in 10 patients, 5each from the intermediate and late groups, therewas focal narrowing of the lumens of interlobularand subpleural lymphatics by sparsely cellular looseconnective tissue (Figure 12).

Chronic Vascular Remodeling

In patients in the late group extensive remodelingof the pulmonary vascular bed had occurred. The ar-teriogram showed narrow preacinar arteries stretchedand splayed about fibrous-walled cysts and dilated airspaces. Beneath the pleura these stretched vesselsfocally had a "picket fence" appearance (Figure 10).In all late group patients tortuous preacinar andintraacinar arteries were present in the arteriogramand appeared histologically as serpentine, kinked andcoiled, thick-walled vessels (Figure 13). These tor-tuous channels were concentrated in regions of denseor irregular fibrosis. An associated histologic findingin the late-stage patients was irregularly distributednests of dilated capillaries that abnormally admittedcontrast medium into the pulmonary veins. In 7 pa-tients this produced a dense, ground-glass back-ground haze in the postmortem arteriogram (Figure14).

Morphometric Findings

Figure 15 shows the arterial concentrations for the3 patient groups. Compared to the early group, theintermediate group had a reduced, and the late stagepatients an increased, mean concentration of intra-acinar arteries. In neither did this reach statistical sig-nificance, because the variance between patients,especially in the late groups, was great.With increasing duration of ARDS there was a

steady reduction in mean external diameter for par-tially and fully muscular arteries (Figure 16). For thefully muscular arteries this difference was significantbetween the early and late groups, and for the par-tially muscular arteries both the early and inter-mediate groups were significantly different from thelate group.As the duration of ARDS increases, the percentage


Figure 6-Acute endothelial injury. Swollen endothelial cells with dilated endoplasmic reticulum (arrows) occlude the capillary lumen. A peri-cyte (P) is adjacent to the thickened basement membrane (B). Granular pneumonocytes (G) with prominent microvilli and lamellar inclusions(L) line the alveolus (A) (16 days, viral pneomonia). (x6500)

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Figure 7-Acute endothelial injury. Early separation of endothelial cell (E) from capillary basement membrane (B) with interposition of fibrinand cellular debris. Mitochondria (M) and cisternae (C) are swollen, but intercellular junctions are still intact (arrows). Platelets (P), fibrin (F),and membrane-bound debris lie within capillary lumen on right (biopsy, Day 10, toxic inhalation). (x6580)

AJP * July 1983


Figure8-Chronic injury. Aprominent endothelial cell (E)narrows the capillary lumenthat is filled by a distortedred blood cell (R). The base-ment membrane (B) is redu-plicated, and there is abun-dant perivascular collagen(C) (25 days after aspiration).(x 6580)

of medial wall thickness increases (Figure 17). If bothacinar and preacinar muscular arteries are combined,this change is significantly different between the earlyand late groups. The trend toward increasing wallthickness, however, was present at each landmarkedlevel of the pulmonary artery (Figure 18). Changes inwall thickness between patients of the early and in-termediate groups were most notable at the preacinarlevel, whereas differences in both preacinar and intra-acinar arteries were significant between the early andlate groups.When one compares individual patients, the var-

iance in the percentage of medial thickness increaseswith duration of ARDS (Figure 19). In the patientsof the early group there is a narrow distribution ofthin-walled arteries. With increasing duration of lunginjury, the range becomes wider and shifts towardgreater medial wall thickness.

Discussion

The term "adult respiratory distress syndrome"designates a clinical illness characterized by acute,catastrophic respiratory failure with hypoxemia, de-creased pulmonary compliance, increased microvas-cular permeability, and diffuse alveolar infiltrates onchest X-ray. Though intrapulmonary processes may

produce this syndrome, it is most puzzling when, asoften happens, it is precipitated by a nonpulmonaryillness such as systemic trauma or sepsis. Despite thediversity of causes, the pathologic picture is fairlyconstant, usually with few hints of the originalcause.15 Pathologically the syndrome can be dividedinto an early, "exudative" phase, which evolves, afterabout a week, into a "proliferative" phase."2-4 In thepresent study we have divided the patients accordingto duration of ARDS, from the onset of severedisease (tracheal intubation) into early, intermediate,and late groups, which correspond with three keystages in the pathologic evolution of the disease -theacute exudative phase of edema and hemorrhage, thestage of exuberant granulation tissue associated withorganization of fibrinous edema, and the stage wherethis edema is converted to dense fibrosis. The de-velopment of pulmonary vascular lesions in ARDSrelates to this time frame. For any patient, the pul-monary vascular lesions correlate with the durationof pulmonary disease rather than its cause.Whereas simple loss of the pulmonary vascular bed

in this syndrome has been previously described,1'8 thewide variety of vascular lesions is herein identified.When related to the progression of disease, new typesof vascular lesions appear even in the intermediateand late phases. While some lesions may represent

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Figure 9-Distorted tortuous pulmonary capillary. E, endothelial cell; R, red blood cell (biopsy, 16 days after trauma). (x6580)

Figure 10- Fibrocellular vascular obliteration. A- Postmortem arteriogram showing marked reduction of filled small vessels and prominentinterlobular septa (16 days, viral pneumonitis). (x 2.4) B - More extensive reduction of filled peripheral arteries due to intimal obliteration.Subpleural branches are stretched about dilated air spaces with a "picket fence" appearance (16 days after toxic inhalation). (x 2.4) C-Severe fibrocellular intimal proliferation in a nonmuscular alveolar wall artery. Note cell in mitosis (arrow). The interstitium is widened bycollagen, edema, and a mononuclear cell infiltrate. Irregular hyperplastic epithelial cells line alveolar spaces (a) (biopsy, Day 21, viral pneumonia).(Toluidine blue, x400)

AJP * July 1983


Figure 11-Venous sclerosis. A-Eccentric fibrous intimal thickening of a pulmonary vein with cellular intra- and perivascular infiltrateof fibroblasts, lymphocytes, plasma cells, and a few neutrophils (36 days after aspiration). (Elastic van Gieson, x 250) B-Lumen of anintralobular vein narrowed by loose connective tissue (20 days after trauma). (Elastic van Gieson, x 250)

the evolution of antecedent injury, others, such aslate-onset acute endothelial injury are probably theresult of superimposed events such as high FIo2 orsuperinfection.

All of these vascular lesions can contribute to pul-monary hypertension. In the early stage, acute endo-thelial injury has been documented ultrastructurallywithin 1 day of the onset of symptoms."6 At the light-microscopic level, intense hemorrhage and edema isassociated with intracapillary engorgement and mi-crovascular thromboemboli. These changes persistinto the intermediate phase when chronic capillarychanges are observed ultrastructurally. This phase isfurther characterized by fibrocellular obliteration ofarteries, veins, and even lymphatics. Often during theintermediate phase, severe pulmonary infection su-pervenes and produces necrotizing vasculitis. Finally,in the late stage, vascular remodeling is associatedwith distorted, tortuous arteries and veins and areduced number of capillaries, which are typicallydilated. Arterial muscularization and neomuscular-ization is identified morphometrically in the interme-diate phase and is pronounced in the late phase.

Thromboembolism

The quantitative methods used in this study Figure 12- Lymphatic duct lumen (L) narrowed by loosely organized,sparsely cellular connective tissue. The surrounding interlobular sep-

demonstrate the importance of thromboemboli tum is fibrotic (20 days after trauma). (Elastic van Gieson, x 250)

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Figure 13-Arterial tortuosity. A- Postmortem arteriogram showing marked arterial tortuosity, increased background haze, and fine arteriesstretched about honeycomb "cysts" (26 days after aspiration). (x 2.4) B -Serpentine acinar arteries are surrounded by organizing fibroustissue (same patient as in A). (Elastic van Gieson, x 100) Figure 14-Capillary dilatation. A-Postmortem arteriogram showing intensebackground haze and venous filling (arrow) (55 days after viral pneumonia). (x 2.4) B1- Nests of dilated capillaries, filled with barium andsurrounded by fibrous tissue (same patient as A). (H&E, x 250)

throughout all stages of disease of diverse causes.The morphologic types of thromboemboli-macro-thrombi, large microthrombi, and capillary thrombi-have been described by Eeles and Sevitt in burnedand traumatized patients.17 As in that study, inARDS, capillary microthrombi are most numerous inthe early stage. Larger microthrombi occur regularlythroughout all stages of disease, whereas macro-thrombi tend to be fewer in the late stage, whichcould indicate either lysis of macrothrombi or, per-haps, that the patients that survive longer have fewerclots in the early stages.We attempted to correlate the extent and types of

thromboemboli found at autopsy with the cause ofthe ARDS, the findings on antemortem balloon oc-clusion pulmonary angiography, and the clinicaldiagnosis of DIC. In our study there was no patternof macro or microthrombosis characteristic of anysingle cause of ARDS. The lung scores for macro-thrombi correlated with filling defects noted on bal-loon occlusion pulmonary angiography; scores formicrothrombi did not correlate as well. Greene et alhave previously reported filling defects in 48% of pa-

tients with ARDS and shown that the presence ofmultiple filling defects is an early indicator of even-tual death.9The clinical diagnosis of DIC by standard screen-

ing tests did not reliably predict thromboemboli atautopsy. Although a clinical diagnosis of DIC was

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Figure 16-Variation in the external diameter of three structural typesof intraacinar arteries with duration of ARDS (mean ± SEM). For par-tially muscular arteries, both early and intermediate groups are sig-nificantly different from the late group (P < 0.05). For muscular arter-ies the early group differs significantly only from the late group (P< 0.01).

associated with at least some thromboemboli, thatdiagnosis did not necessarily indicate large numbersof thromboemboli. There were also 6 patients inwhom the diagnosis of DIC could not be made bylaboratory screening tests but who also had throm-boemboli at autopsy. If more sensitive coagulationtests are used, most patients with ARDS show evi-dence of intravascular clotting.18 In retrospectivestudies such as this, however, the timing of the co-agulation blood sample as well as the interval be-tween this sample and death will obviously affect thecorrelations.The origin and pathogenicity of thromboemboli in

ARDS is controversial. Eeles and Sevitt believedthat, in burn and trauma patients, both macrothrom-bi and microthrombi originated as systemic venousthrombi. They believed capillary thrombi were re-lated to hypercoagulation immediately after severeinjury. In their study this view was supported by thefinding of deep vein thrombosis in the extremities ofmost patients with pulmonary thromboemboli. 17Others have also demonstrated that, particularlyafter shock or trauma, microemboli may originateperipherally.3-4-19 On the other hand, pulmonary en-dothelial injury in ARDS can cause localized intra-vascular coagulation within the lung.20-21 Further-more, Boggis et al have documented in situ micro-thrombosis after experimental lung contusion insheep.22 The present study cannot resolve the prob-lem of the origin of pulmonary thromboemboli in

ARDS, because it is impossible on morphologicgrounds to distinguish embolic clots from those de-veloping in situ.

Microemboli have been assigned a primary patho-genetic role in producing lung injury, especially inARDS following trauma and shock.3 4-23'24 We couldnot reach a firm conclusion about the role of micro-emboli as mediators of primary lung injury in all in-stances of ARDS. The absence of thromboemboli insome patients, including 1 early group patient withfindings typical of the exudative phase, and the pres-ence of severe lung injury in a patient with aplasticanemia suggest that microemboli are not the onlymediators of acute lung injury in this disease. Only3 patients in our series had numerous capillarythrombi, the form most likely to produce diffuse lunginjury. The possibility, however, that capillary mi-crothrombi were present and subsequently lysed inpatients with longer survival cannot be excluded.Whether or not they represent a primary triggeringmechanism, thromboemboli can contribute to lunginjury at any stage, further reducing the pulmonaryvascular bed and producing lung necrosis throughischemia.

Endothelial Injury

While acute endothelial injury has been reported asan early event in ARDS, an important finding in thisstudy was the presence of acute changes even in theintermediate and late stages. The cellular changes

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Figure 17-Variation in the percentage of medial wall thickness ofpartially and fully muscular arteries with duration of ARDS (mean + -SEM). For partially muscular arteries the early group differs signifi-cantly from the late group (P < 0.05). For muscular acinar arteriesboth the early (P <0.01) and intermediate groups (P < 0.05) differ sig-nificantly from the late group, whereas for preacinar arteries, the earlygroup differs from both the intermediate group (P < 0.05) and thelate group (P < 0.01).

Vol. 112 * No. 1

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Figure 18-Variation in the percentage of medial wall thickness ofmuscularized pulmonary arteries at different anatomic levels withduration of ARDS. The early group differs significantly from the lategroup at the alveolar duct (P < 0.05) and respiratory bronchiolar levels(P < 0.01). There is significant difference between the intermediateand late groups only at the respiratory bronchiolar level (P < 0.05).

were similar regardless of the cause of ARDS and re-

semble those reported in ARDS due to sepsis, shock,or thermal injury.8 16.25 Similar capillary endothelialchanges occur in humans and animals exposed totoxic levels of oxygen26-29 and in many different ex-

perimental models of acute lung injury.30-35 The pres-

ence of acute changes long after the initial injury sug-

gests additional noxious factors, such as a high FIo2,may produce additive injuries in later stages of thedisease. In the intermediate and late groups chronicchanges such as hypertrophic endothelial cells andthickened, reduplicated basement membranes com-

promise capillary lumens.

Fibrous Intimal Proliferative Lesions

Throughout the intermediate and late stages therewas reduced filling of small arteries in the post-mortem arteriogram. Fibrocellular intimal prolifera-tion of arteries contributes to the reduction in cross-

sectional luminal area and is a nonspecific findingthat can be associated with severe pulmonary hyper-tension of various types, interstitial fibrosis, or pul-monary inflammation.36 A similar intimal change,associated with reduced angiographic filling, hasbeen described in the experimental animal breathingoxygen for 28 days.37

In ARDS a similar, but generally less cellular in-timal proliferation occurs focally in pulmonaryveins. Physiologically, venous obstruction can con-

tribute to elevated microvascular pressure and forcefluid into the extravascular space. Obstruction oflymphatics secondary to coagulation of proteina-ceous edema will further impede removal of inter-

stitial fluid. The endolymphatic obstruction observedin this study, involving relatively large interlobularchannels, suggests a more widespread functional ob-struction of small intralobular lymphatics.

Chronic Vascular Remodeling

Extensive pulmonary vascular remodeling occursin the intermediate and chronic phases of ARDS.Preacinar arteries, stretched and distorted by sur-rounding parenchymal fibrosis, create unusual arteri-ographic patterns. Arterial tortuosity is often exten-sive. It appears to be a nonspecific vascular distortionby forces exerted via irregular, contracting fibroustissue, an "accordion effect." Changes of vascularwall compliance by chronic injury could also, in part,contribute to this appearance. In patients in the latestage, pulmonary capillaries are markedly dilated,forming irregular cirsoid nests. The increased arterialconcentrations we measured in patients in the latestage probably reflects the abnormally dilated vessels,and not a restoration or regrowth of normal arteries.

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Figure 19- Frequency distribution of the percentage of medial wallthickness of muscular pulmonary arteries for individual lungs, ar-ranged according to increasing duration of ARDS. Representative pa-tients have been selected to show the trend of changes.

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----r-

AJP * July 1983

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Vol. 112 * No. 1 VASCULAR LESIONS OF ARDS 125

Muscularization and Neomuscularization

The present morphometric findings extend those ofSnow et al.7 and show for the first time a significantincrease in arterial muscularity with time duringARDS. The decreased mean external diameter offully and partially muscular arteries in patients in theintermediate and late stages suggests that smallerpartially muscular or nonmuscular arteries have been"recruited" into the muscular group by peripheral ex-tension of muscle into smaller arteries than is nor-mal. The presence of a significant difference in medialwall thickness between the early and intermediategroups only at the preacinar level suggests furtherthat muscularization starts centrally.

There are several possible mechanisms contribut-ing to increased arterial muscularization in ARDS.Hypoxia, which is present early and may be eitherdiffuse or localized within the lung in ARDS, causesmuscular hypertrophy and extension in man and ex-perimental animals.3840 Pulmonary hypertension it-self may lead to both types of muscularization, asseen in patients with congenital heart disease andhigh-flow left-to-right shunts.41 In the irregularly re-duced vascular bed of ARDS there may be localizedincreased flow. Finally, oxygen toxicity may play akey role in both the acute and more chronic vascularlesions. In chronic experimental hyperoxia arterialmuscularization and muscular extension has been ob-served.37 The net effect of increased mural muscula-ture will be to further reduce the vascular lumendiameter and possibly increase vascular tone and re-activity.

Clinical Implications

The vascular lesions of ARDS correlate more withthe duration of disease than with the particularcause. They vary in their nature and severity, arelargely nonspecific, and do not identify any spe-cific mechanism of injury, but are compatible withthe sequelae of different types of vascular insult. Thefindings in this study, however, have important ther-apeutic implications. Diagnosis and treatment ofthromboembolic disease with anticoagulant or throm-bolytic therapy could preserve segments of the pul-monary artery. Similarly, treatment of infectiouscomplications by appropriate antibiotics should re-duce vasculitis. Minimizing exposure to high levels ofoxygen, a potent endothelial toxin, should also limitvascular injury. An understanding of the basic mech-anisms of lung injury in ARDS may eventually leadto the development of specific pharmacologic agentsto protect the vascular endothelium from the noxious

effects of mediators such as superoxide radicals,vasoactive peptides, and metabolites of arachidonicacid.42 Finally, early intervention in ARDS is essen-tial, because many of the chronic vascular changessuch as capillary or lymphatic obliteration and vas-cular tortuosity appear to be irreversible, contributeto progressive lung destruction, and prevent survival.

References

1. Zapol WM, Snider MT: Pulmonary hypertension insevere acute respiratory failure. N Engl J Med 1977,296:476-480

2. Pontoppidan H, Wilson RS, Rie MA, Schneider RC:Respiratory intensive care. Anesthesiology 1977,47:96-116

3. Blaisdell FW, Lim RC, Stallone RJ: The mechanism ofpulmonary damage following traumatic shock. SurgGynecol Obstet 1970, 130:15-22

4. Saldeen T: The microembolism syndrome. MicrovascRes 1976, 11:227-259

5. West JB, Dollery CT, Heard BE: Increased pulmonaryvascular resistance in the dependent zone of the iso-lated dog lung caused by perivascular edema. Circ Res1965, 17:191-206

6. Zapol WM, Kobayashi K, Snider MT, Greene R,Laver MB: Vascular obstruction causes pulmonaryhypertension in severe acute respiratory failure. Chest1977, 71S(suppl):306-307

7. Snow RL, Davies P, Pontoppidan H, Zapol WM, ReidLM: Pulmonary vascular remodelling in adult respira-tory distress syndrome. Am Rev Respir Dis 1982,126:887-892

8. Bachofen M, Weibel ER: Alterations in gas exchangeapparatus in adult respiratory insufficiency associatedwith septicemia. Am Rev Respir Dis 1977, 116:589-615

9. Greene R, Zapol WM, Snider MT, Reid L, Snow R,O'Connell RS, Novelline RA: Early bedside detectionof pulmonary vascular occlusion during acute respira-tory failure. Am Rev Respir Dis 1981, 124:593-601

10. Dunnill MS: Quantitative methods in the study ofpulmonary pathology. Thorax 1962, 17:320-328

11. Snedecor GW, Cochran WG: Statistical Methods. 6thedition. Ames, Iowa, The Iowa State University Press,1967, p 273

12. Katzenstein AL, Bloor C, Liebow AA: Diffuse alveolardamage, the role of oxygen, shock and related factors.Am J Pathol 1976, 85:210-228

13. Orell SR: Lung pathology in respiratory distress fol-lowing shock in the adult. Acta Pathol MicrobiolScand 1971, 79:65-76

14. Nash G, Blennerhassett JB, Pontoppidan H: Pulmo-nary lesions associated with oxygen therapy and arti-ficial ventilation. N Engl J Med 1967, 276:368-374

15. Pratt PC, Vollmer RT, Shelburne JD, Crapo JD: Pul-monary morphology in a multihospital collaborativeextracorporeal membrane oxygenation project: I.Light microscopy, Am J Pathol 1979, 95:191-208

16. Schnells G, Voigt WH, Redl H, Schlag G, Glatzl A:Electron microscopic investigation of lung biopsies inpatients with post traumatic respiratory insufficiency.Acta Chir Scand (S) 1980, 449:9-20

17. Eeles GH, Sevitt S: Microthrombosis in injured andburned patients. J Pathol Bacteriol 1967, 93:275-293

18. Carvalho A, Greene R, Boggis C, Quinn D, Rie M,Zapol W: Intravascular coagulation (IVC) with fibrin-olysis in patients with acute respiratory failure (ARF)

126 TOMASHEFSKI ET AL AJP * July 1983

and angiographic pulmonary vascular occlusion (Ab-str). Am Rev Respir Dis 1982, 125(suppl):93

19. Blaisdell FW, Lim RC, Amberg JR, Choy SH, HallAD, Thomas AN: Pulmonary microembolism, a causeof morbidity and death after major vascular surgery.Arch Surg 1966, 93:776-786

20. Bone RC, Francis PB, Pierce AK: Intravascular coagu-lation associated with the adult respiratory distress syn-drome. Am J Med 1976, 61:585-589

21. Schneider RC, Zapol WM, Carvalho AC: Platelet con-sumption and sequestration in severe acute respiratoryfailure. Am Rev Respir Dis 1980, 122:445-451

22. Boggis C, Greene R, Schuette A, Tomashefski J, JonesR: Pulmonary arterial occlusive disease in experimen-tal lung contusion (Abstr). Invest Radiol 1982, 17:58

23. Lough J, Moore S: Endothelial injury induced bythrombin or thrombi. Lab Invest 1975, 33:130-135

24. Costabella PM, Lindquist 0, Kapanci Y, Saldeen T:Increased vascular permeability in the delayed micro-embolism syndrome, experimental and human find-ings. Microvasc Res 1978, 15:275-286

25. Nash G, Foley FD, Langlinais PC: Pulmonary intersti-tial edema and hyaline membranes in adult burn pa-tients, electron microscopic observations. Hum Pathol1974, 5:149-159

26. Gould VE, Tosco R, Wheelis RF, Gould NS, KapanciY: Oxygen pneumonitis in man, ultrastructural obser-vations on the development of the alveolar lesions. LabInvest 1972, 26:499-508

27. Kapanci Y, Weibel ER, Kaplan HP, Robinson FR:Pathogenesis and reversibility of the pulmonary lesionsof oxygen toxicity in monkeys: II. Ultrastructural andmorphometric studies. Lab Invest 1969, 20:101-116

28. Kistler GS, Caldwell PRB, Weibel ER: Developmentof fine structural damage to alveolar and capillary lin-ing cells in oxygen poisoned rat lungs. J Cell Biol 1967,32:605-628

29. Crapo JD, Peters-Golden M, Marsh-Salin J, Shel-burne JS: Pathologic changes in the lungs of oxygenadapted rats, a morphometric analysis. Lab Invest1978, 39:640-653

30. Connell RS, Swank RC, Webb MC: The developmentof pulmonary ultrastructural lesions during hemor-rhagic shock. J Trauma 1975, 15:116-129

31. Connell RS, Swank RL: Pulmonary microembolismafter blood transfusions, an electron microscopicstudy. Ann Surg 1977, 177:40-50

32. Ratliff NB, Wilson JW, Hackel DB, Martin A: Thelung in hemorrhagic shock: II. Observations on alveo-lar and vascular ultrastructure. Am J Pathol 1970,58:353-373

33. Fishman AP: Electron microscopic alterations at thealveolar level in pulmonary edema. Circ Res 1967,21:783-797

34. Boatman ES, Frank R: Morphologic and ultrastruc-tural changes in the lungs of animals during acute ex-posure to ozone. Chest 1974, 65(suppl):9-11

35. Alexander IGS: The ultrastructure of the pulmonaryalveolar vessels on Mendelson's (acid pulmonary aspi-ration) syndrome. Br J Anaesthesiol 1968, 40:408-414

36. Wagenvoort CA, Wagenvoort N: Pathology of pulmo-nary hypertension. New York, John Wiley & Sons,1977, pp 273-282

37. Jones R, Zapol WM, Reid L: Progressive and regres-sive structural changes in rat pulmonary arteries duringrecovery from prolonged hyperoxia (Abstr). Am RevRespir Dis 1982, 125(suppl):227

38. Naeye RL: Hypoxemia and pulmonary hypertension.Arch Pathol Lab Med 1961, 71:447-452

39. Hislop A, Reid L: New findings in pulmonary arteriesof rats with hypoxia-induced pulmonary hypertension.Br J Exp Pathol 1976, 57:542-553

40. Meyrick B, Reid L: The effect of continued hypoxia onrat pulmonary artery circulation: An ultrastructuralstudy. Lab Invest 1978, 38:188-200

41. Hislop A, Haworth SG, Shinebourne EA, Reid L:Quantitative structural analysis of pulmonary vesselsin isolated ventricular septal defect in infancy. BrHeart J 1975, 37:1014-1021

42. Hempel FG, Lenfant CJM: Current and future re-search on adult respiratory distress syndrome. SeminRespir Med 1981, 11:165-172

AcknowledgmentsThe authors thank Dr. Antonio Perez, who reviewed the

electron micrographs, and Peter Nowak, who preparedthem, Tudor Williams and Marita Bitans for photographicassistance, and Pamela Conze and Priscilla Stottlemire forsecretarial help. The authors are also deeply appreciative ofthe cooperation of Drs. Robert McCluskey and EugeneMark of the Department of Pathology, MassachusettsGeneral Hospital.

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