pulmonary at necropsy: a combined · j. clin. path., 1975, 28, 357-366 pulmonaryoedemaat necropsy:...

J. clin. Path., 1975, 28, 357-366

Pulmonary oedema at necropsy: a combinedpathological and radiological method of studyGERARD SLAVIN, LOUIS KREEL, AMANDA HERBERT, AND BRENDA SANDIN

From the Departments of Histopathology and Radiology, Northwick Park Hospital and Clinical ResearchCentre, Harrow, Middlesex

sYNoPsis Fixation of lungs at necropsy by inflation with formaldehyde vapour was used in a

combined radiological and pathological study of pulmonary oedema. Pulmonary oedema was foundin 79% of lungs examined. The earliest phases affect the interstitial tissue with oedematous connec-

tive tissue planes and distension of pulmonary lymphatics. These changes may be associated with re-

duction in the compliance of the lung. Alveolar filling is a late stage in the accumulation ofoedemafluid in the lungs.

Pulmonary oedema is one of the commonest lesionsseen at necropsy. It occurs in association with adiversity of pathological conditions and often as aterminal event. Cameron (1948) showed that thefrequency of severe pulmonary oedema was markedin association with cardiovascular disease, cerebrallesions, and trauma such as multiple fractures, butthat it was common also in the terminal phase ofmany illnesses. However, its frequency and itsapparently unexciting histological features havediverted the interest of morbid anatomists frompulmonary oedema. It is a secondary phenomenonbut it is not of secondary importance for it givesrise to gross disturbances in pulmonary functionand may be the immediate cause of death.Pulmonary oedema at necropsy may be estimated

inexactly by gross weighing of the excised lungs andby the demonstration of free fluid exuding from thecut surfaces of the lungs. Histological examinationconfirms the presence of pulmonary oedema butunless multiple sections are taken in a systematicfashion the sum of these methods may offer littleor no information concerning the amount or distri-bution of oedema in the lung. Moreover, with thedevelopment of intensive care units, pathologistsare required to provide services on patients whosepulmonary function has been monitored in detailup to the time of death. In these patients standardnecropsy procedures are particularly inadequate inthe assessment of interstitial pulmonary oedemawith a minor or no alveolar component.Lungs fixed by a formaldehyde vapour inflation

technique (Wright, Slavin, Kreel, Callan, and Sandin,1974) without any fluid condensation or instillationReceived for publication 13 January 1975.

into the lungs have been studied. The lungs arefixed in a position of inflation; radiolucency of thelungs is maintained, and combined radiological andpathological studies of the excised lungs are possible.This paper records experience of this technique inthe demonstration of pulmonary oedema.

Material and Methods

Lungs from 150 unselected clinical necropsies wereexamined after formaldehyde vapour fixation. Mostnecropsies were performed more than 24 hoursafter death. Coroner's necropsies were not includedin the study. The period of fixation was usuallyovernight. The fixed lungs were x-rayed in antero-posterior and lateral views. The lungs were thensliced with a ham knife at IP0 cm and the sliceswere radiographed again. Tissue blocks for histo-logical examination were selected from the naked-eye lesions in the lung slices, from radiologicallyobserved lesions, and from multiple random sites.Correlations were made between radiological ap-pearances and the subsequent histological demon-stration of pulmonary oedema so that with experi-ence the radiological features were recognized andused to map the anatomical locations of pulmonaryoedema. In addition, vapour fixation allowed mor-phological studies of pulmonary oedema in inflatedlungs undistorted by the addition of large quantitiesof liquid fixative.

Results

Pulmonary oedema was seen radiologically andconfirmed by microscopy in 106 of the 150 lungs

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Gerard Slavin, Louis Kreel, Amanda Herbert, and Brenda Sandin

Total lungs examined 150Oedema not identified 31 21',Oedema detected by radiology, confirmed by histology --106Interstitial oedema only 5 3 %Interstitial and alveolar oedema 101 67%Oedema identified by histology alone 13 9',

Table I Frequency ofpulmonary oedema

examined. In 13 lungs oedema was demonstratedhistologically which had not been seen on theradiographs (table I). These figures represent thepresence or absence of oedema, and no attempt tograde the severity of the process was made. Inparticular, the interstitial component was frequentlywell marked but in association with only a minordegree of alveolar filling. A quantitative study of thedistribution of pulmonary oedema and its relativeamounts in the various compartments of the lungsis in progress (Slavin, Herbert, and Kr_~el, 1975).

MACROSCOPIC APPEARANCESOn slicing the lung prepared by this technique fluiddoes not run from the cut surface as in the markedlyoedematous fresh lung. The surfaces are moist, but

in areas which subsequently prove to have markedhaemodynamic pulmonary oedema a brown dis-colouration of the surface may be seen. Interstitialand septal oedema may be recognized by undueprominence of rather gelatinous bands or septa.Oedema may also be recognized by a change in thetexture of the lungs which feel stiff and firmer thanusual.

RADIOLOGYRadiological examination of the lungs whole andsliced shows two basic morphological patterns:

(a) There may be undue prominence of septal linesand interstitial fascial sheaths or paravascularconnective tissue planes, which correspond tointerstitial oedema and are seen as various types oflinear opacities (fig 1).

(b) Small punctate opacities may produce awhite 'ground glass' appearance which correspondsto the presence of intra-alveolar oedema. Thisappearance typically spares the peripheral cortex,and such sparing may help radiographic distinctionbetween pneumonic consolidation and confluentoedema (fig 2).

Fig I Radiograph of a 1 cm slice of lung showingmarked interstitial pulmonary oedema. The oedemalines (arrows) are of variable calibre and extendbetween pleura, bronchovascular bundles, and veins.They are distinguishedfrom arteries (a) which areregularly distributed and taper and branch withoutreaching the pleural surface.

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Pulmonary oedema at necropsy: a combinedpathological and radiological method of study

Fig 2 There is intra-alveolar oedemashowing multiple tiny pinpont opacities andproducing a ground glass appearanceobscuring the vascular pattern when itbecomes confluent. Note how the peripheralpart of the lung is relatively spared byalveolar oedema.

The radiological lines are an early manifestationof pulmonary oedema and are equivalent to A, B,and D lines recognized in life (Kerley, 1962; Kreel,Slavin, Herbert, and Sandin, 1975). They may beseen as the sole manifestation of pulmonary oedemaor in association with the ground glass appearancein more severe cases. The localization of suchradiological lines is partly determined by preformedsepta and partly by fascial planes within the inter-stitium of the lung. Thus they are frequently seenat the angles of the lungs where fascial septa arecommon (Reid, 1959). Oedematous paravasculartissues may also give rise to linear shadows, andfrequently thick band-like oedematous lines appearto originate from paravascular regions. The punctateground glass appearance may be seen as a generalizedor regional phenomenon corresponding to alveolaroedema in large areas of the lungs. It is consistentlymore marked at the bases of the lungs and increasesin the posterior and upper zones when the oedemabecomes more generalized. Except in very grosspulmonary oedema, punctate shadowing tends to bemuch less in the anterior parts of the lung and in themiddle lobe. By contrast, thick band shadows ofinterstitial pulmonary oedema (D lines) are moremarked anteriorly although only minimal or no

alveolar oedema is recognized in the adjacent lungon the radiographs (Kreel et al, 1975). Intra-alveolaroedema may also be recognized as a component ofa local lesion in association with a pulmonary infarctor inflammatory disease.

HISTOLOGICAL APPEARANCESThis method of preparation and block selectiondraws attention to early interstitial forms of pul-monary oedema as well as the later forms wherealveolar flooding is easily recognizable. In staticmorphological studies of necropsy material it isnot possible to ascertain the exact sequence of fluidaccumulation but it is possible to recognize character-istic morphological changes due to excess fluid inthe various tissues of the lung and to correlate thesewith the clinical and radiological features.

(1) There is an expansion of the perivascular,peribronchiolar, and interstitial connective tissuespace by oedema fluid. Such fluid may be largelyconfined to the periarterial sheath (fig 3). Fascialplanes and septa may be seen swollen with eosino-philic oedema fluid (fig 4). Lymphatics in theseconnective tissue planes may be dilated, and similarsubpleural lymphatics are frequently prominentbeneath oedematous pleura (fig 5). These changes

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Fig 3 Interstitial oedema in paravascular connective tissue. Note the small amount of alveolar oedemapredominantlyseen in the angles ofalveolar sacs. (Haematoxylin and eosin x 55).

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anticipate the expansion of alveolar wall interstitialspace, and swollen connective tissue planes may beseen next to essentially normal alveoli (fig 6).

(2) Alveolar wall thickening with capillary con-gestion is noted but usually in association with

(3) alveolar filling: the alveoli appear to fill withoedema fluid individually. Normal unfilled alveolimay be seen next to alveoli completely filled byfluid. Intermediate, half-filled alveoli are infrequent,but some alveoli may show arcuate zones of oedemaat the corners of the alveolus while the remaindercontains air (fig 7). The extent of alveolar filling isvariable, but ultimately confluent pulmonary oedemaoccurs (fig 8).Examination of the lungs by this technique is

valuable as a purely morphological exercise. It isparticularly valuable if the material is reviewed inconjunction with in vivo pulmonary function testsand in vivo and postmortem radiology.

Case Report

A 22-year-old pregnant woman was admitted tohospital with pre-eclamptic toxaemia. She suffereda cardiac arrest on the ward and was resuscitatedbut remained comatose. Respiration was maintained

by intermittent positive pressure. No recovery ofcerebral function occurred and she died after 10days' maintenance on the respirator. During theperiod of assisted respiration the lungs became lesscompliant, requiring increased inflation pressure forthe same or a reduced tidal volume (table II).Examination of the lungs after death by a com-

bined radiological and histological technique showedonly minor or moderate quantities of oedema fluidin the alveoli but gross interstitial oedema withdistended interstitial septa, particularly anteriorly

Date Tidal Vol (ml) Inflation Pressure Compliance(cmH,O) (ml/cmH,O)

25 March 500 18 2526 March 500 22 2227 March 500 24 2128 March 500 24 2129 Marcham 500 24 21pm 500 26 19

30 March5.0 am 500 30 17

10.0 am 400 30 13Death

Table II Evidence of increasing lung stiffness duringintermittent positive pressure respiration

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Fig 7 Intra-alveolar oedema. Fluid-filled alveoli are seen adjacent to normal air-filled sacs. Partially filled sacs arescanty but note presence ofsmall fluid arcs at angles of alveoli. (H and E x 80)

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Pulmonary oedema at necropsy: a combined pathological and radiological method of study

Fig 8 Confluent oedema with intra-alveolar flooding. (H and E x 80)

and at the angles of the lungs (fig 9 a-d). It was

concluded that the decreased compliance was

accounted for at least in part by the marked oedemain the interstitial component.

Discussion

The frequency of pulmonary oedema in thesenecropsies (79%) is greater than that in the seriesreported by Cameron (1948; 65 %) using conventionaltechniques though there is some selection in our

material in the exclusion of coroner's cases. Thisincrease may reflect the help given by radiographsof lung slices in selecting blocks for histologicalexamination and particularly in the recognition ofdistended and oedematous connective tissue planesbefore the phase of alveolar flooding.The lung is not a dry organ but the pathways of

normal fluid movements are not clear. Fluid leavingnormal alveolar vessels, either capillaries or venules,passes into the interstices of the alveolar wall tolymphatics in interstitial tissue. This fluid does notnormally enter the alveolar spaces but may move

under the direction of a subatmospheric pressure inthe interstitial tissue (Staub, 1970; Staub, 1974),reaching the systemic circulation via pulmonarylymphatics.

Pulmonary oedema occurs when there is anexcess accumulation of fluid inthevariouspulmonarycompartments. Haemodynamic oedema may arisein association with increased left atrial pressure asin congestive cardiac failure, while toxins such asalloxan (Cottrell, Levine, Senior, Wiener, Spiro,and Fishman, 1967), alpha-naphthyl thiourea, highconcentrations of oxygen (Meyrick, Miller, andReid, 1972), and bacterial toxins (Finegold, 1967)may induce pulmonary oedema following directdamage to endothelial cells.

In experimental animals haemodynamic pul-monary oedema appears to result from an accen-tuation of the normal process of fluid exchangeswithin the lung (Cottrell et al, 1967; Szidon, Pietra,and Fishman, 1972). There is an increase in the rateof fluid and protein flow before any recognizable in-crease in extravascular fluid content. The earliestchanges seen on electronmicroscopyshow that excesswater accumulates in those portions of alveolar septarich in connective tissue fibres. Such early changes arenot visible by light microscopy but in dogs lightmicroscopy shows that pulmonary oedema developsin a constant morphological sequence (Staub, Nagano,and Pearce, 1967). There is expansion of the periven-ous and peribronchiolar sheaths by oedema fluidand distension of septal lymphatics. Only at a late

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Fig 9a Fig 9bFig 9a Frontal view ofa formaldehyde vapour inflated right lung showing moderate basal oedema seen as a groundglass whiteness. Multiple oedema line shadows are also present.Fig 9b Lateral view showing moderate posterior basal intra-alveolar oedemna which decreases from the base towardsthe upper lobe. Note the thick bands of interstitial oedema shown anteriorly (black arrow head) but without intra-alveolar component.

stage does fluid fill the alveolar spaces. In pulmonaryoedema due to toxic endothelial damage markedinterstitial oedema is present and precedes theformation of alveolar fluid (Finegold, 1967; Meyricket al, 1972). These experimental studies haveprovided strong evidence that the loose interstitialconnective tissue space is a preferential site ofinitial fluid accumulation in pulmonary oedema,both haemodynamic and toxic in origin.By contrast, morphological descriptions of pul-

monary oedema in man lay relatively minor stress

on the interstitial component and place muchmore emphasis on late stage flooded, fluid-filledalveoli (Spencer, 1968; Roberts, 1970; Millard, 1971).The same emphasis is reflected in standard clinicaltexts (Braunwald, 1974) in which signs and symptomsof established pulmonary oedema are stressed at theexpense of the signs of early pulmonary oedema.Some change in attitude has developed with thegrowth of intensive care units. Pulmonary inter-stitial oedema is marked in burned and shockedpatients (Nash, Foley, and Langlinais, 1974), and

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Pulmonary oedema at necropsy: a combined pathological and radiological method of study

Fig 9c I cm slice of right lung inlateral view showing very thick bands ofinterstitial oedema. There are also manythin interstitial lines but note the relativelack of shadowing due to intra-alveolarpulmonary oedema.

Fig 9d There is gross interstitialoedema with thickened septa connectingpleura, bronchovascular bundles, andveins. (H and E x 4)

Fig. 9c

Fig. 9d

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Gerard Slovin, Louis Kreel, Amnanda Herbert, and Brenda Sandin

it may be that the alterations of compliance as wellas alterations in gas exchange are due to the accumu-lation of fluid about small airways (Pietra, 1974).

Satisfactory morphological examination of thelungs for oedema must direct attention to changesin the interstitial tissues as well as to those occurringin the alveoli. Such examination needs to be atmacroscopic level to establish the anatomicaldistribution of oedema supplemented by histo-logical examination to ascertain the exact micro-scopical location of the excess fluid. Fixation withformaldehyde vapour leaves the lungs in a positionof inflation and with maintenance of in vivo radio-lucency. In lungs with pulmonary oedema post-mortem radiology clearly demonstrates interstitialoedema in the form of Kerley's A and B lines, byD lines, and by widening of bronchovascularbundles. Alveolar oedema is manifested by apunctate ground glass opacity. A series of films of1 cm slices form a permanent record mapping thedistribution of the oedema in 'anatomical tomo-grams'. Moreover blocks for histological examina-tion may be taken in conjunction with and as acontrol of the radiological appearances.The development of pulmonary oedema in a

single patient cannot be studied but some dynamicaspects may be inferred by consideration of thestatic patterns recognized in films from manypatients with various degrees of oedema. There isan initial prominence of interstitial lines followedby intra-alveolar oedema. These changes are mostmarked at the bases and posterior parts of the lung,extending in more severe cases to the upper anteriorparts of the lung in a regular sequence. Too fewcases have as yet been studied to identify a differentmorphological pattern of development between thehaemodynamic pulmonary oedema associated withcongestive cardiac failure and those cases associatedwith endothelial damage due to toxins as in Gram-negative septicaemia.The combined radiological and histological

features seen in these lungs emphasize that in manas in experimental animals the earlier phases ofpulmonary oedema seen by light microscopy affectthe interstitial tissue, and that alveolar filling is alate stage in the accumulation of excess water inthe lungs. Clinical recognition of this interstitialphase is difficult and imprecise. Changes in mechan-ical properties of the lungs such as decreasedcompliance may be a pointer, especially if changesare measured serially in an individual patient.Improved in vivo radiological techniques have beenstimulated by these combined studies (Kreel et al,1975) and are helpful in the early recognition ofinterstitial oedema, but all such methods needclinicopathological correlations in cases followed to

necropsy. If pathologists are to be of meaningfulhelp in such studies they must adapt their techniquesto demonstrate the earlier stages of interstitialoedema as well as the more easily discerned alveolarflooding and to delineate accurately the anatomicaldistribution of such oedema in the pulmonarytissues.

We wish to thank Miss Christine Bateman for thepreparation of the histological sections.

References

Braunwald, E. (1974). Heart failure. In Harrison's Principlesof Internal Medicine, edited by W. M. Wintrobe, G. W.Thorner, R. D.'Adams, E. Braunwald, K. J. Isselbacher, andR. G. Petersdorf, 4th ed., pp. 1117-1127. McGraw-Hill,New York.

Cameron, G. R. (1948). Pulmonary oedema. Brit. med. J.,1, 965-972.

Cottrell, T. S., Levine, 0. R., Senior, R. M., Wiener, J.,Spiro, D., and Fishman, A. P. (1967). Electron microscopicalterations at the alveolar level in pulmonary edema.Circulat. Res., 21, 783-797.

Finegold, M. J. (1967). Interstitial pulmonary edema. Lab.Invest., 16, 912-924.

Kerley, P. (1962). Occupational diseases of lungs. In TextBook of X-ray Diagnosis, edited by S. C. Shanks andP. Kerley, 3rd ed., vol. 2. Lewis, London.

Kreel, L., Slavin, G., Herbert, A., and Sandin, B. (1975).Intralobar septal oedema: D Lines. Clin. Radiol. (Inpress).

Meyrick, B., Miller, J., and Reid, L. (1972). Pulmonaryoedema induced by ANTU, or by high or low oxygenconcentrations in rat. Brit. J. exp. Path., 53, 347-358.

Millard, M. (1971). Lung, pleura and mediastinum. InPathology, edited by W. A. D. Anderson, 6th ed.,vol. 2, pp. 875-997. Mosby, St. Louis.

Nash, G., Foley, F. D., and Langlinais, P. C. (1974). Pulmon-ary interstitial edema and hyaline membranes in adultburn patients. Hum. Path., 5, 149-160.

Pietra, G. G. (1974). The lung in shock. Hum. Path., 5,121-122.

Reid, L. (1959). The connective tissue septa in the adulthuman lung. Thorax, 14, 138-145.

Roberts, K. B. (1970). Oedema. In General Pathology,edited by Lord Florey, 4th ed., pp. 370-393. Lloyd-Luke,London.

Slavin, G., Herbert, A., and Kreel, L. (1975). Unpublisheddata.

Spencer, H. (1968). Pathology, of the Lung, 2nd ed. Per-gammon Press, Oxford.

Staub, N. C. (1970). The pathophysiology of pulmonaryedema. Hum. Path., 1, 419-432.

Staub, N. C. (1974). Pulmonary edema. Physiol. Rev., 54,678-811.

Staub, N. C., Nagano, H., and Pearce, M. L. (1967).Pulmonary edema in dogs, especially the sequence offluid accumulation in lungs. J. appl. Physiol., 22, 227-240.

Szidon, J. P., Pietra, G. G., and Fishman, A. P. (1972).Alveolar-capillary membrane and pulmonary edema.New Engl. J. Med., 286, 1200-1204.

Wright, B. M., Slavin, G., Kreel, L., Callan, K., and Sandin,B. (1974). Postmortem inflation and fixation of humanlungs. Thorax., 29, 189-194.

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