J Clin Pathol 1981 ;34:1147-1154

Effect of oxygen on the lungs after blast injury andburnsPS HASLETON, P PENNA, J TORRY

From the Departments ofPathology and Anaesthetics, University Hospital of South Manchester andDepartment ofPathology, Royal Albert Edward Infirmary, Wigan

SUMMARY In March 1979 there was an explosion in a coalmine in Lancashire. As a result three menwere found dead down the mine and a further seven men, all with extensive burns, died between thethird and thirteenth day after the explosion. The lungs were studied in all the cases. Pulmonaryinfection was the commonest cause of death. Despite high levels of oxygen being given to theseseven men, only one case showed a focal intra-alveolar fibrosis. In this case the inspired oxygen

requirement came down before death. The toxicity of oxygen in the short term management ofpatients with severe trauma is questioned.

Golbourne is a Lancashire village lying midwaybetween Wigan and Warrington. Nearly 900 menfrom the village and surrounding area work in thecolliery.On the night of 17th March 1979, a routine

inspection revealed a breakdown in several venti-lation fans in one of the development seams. The fanwas only suspended by one chain and there wasdamage to the fan cable entry. The following day aneleven strong team was sent below to repair the fans.During this operation there was an electric sparkbetween two exposed live connector pins. Thisspark ignited the firedamp that had built up during10 to 15 hours when there had been no ventilation inthe mine.A sheet of fire spread down the mine followed by

an explosion in the residual methane/air mixture.There was much damage. Three men were found deadand a further eight brought to the surface andtransferred to the Burns Unit at Withington Hos-pital. Seven of these men died between the third andthirteenth day after the explosion.During their stay in hospital the men were treated

in the Intensive Care Unit. Oxygen formed one of themainstays of treatment. The pulmonary changesfound in all the patients, both those found dead andthose dying in hospital, are described. In particularthe relation between the amount of oxygen given and

Accepted for publication 27 April 1981

the development of pulmonary fibrosis is examined.

Clinical details

All the men were severely burnt. In most of the casesthe burns were third degree. In addition there weremultiple fractures, including a fractured skull in onecase. The age of the cases, percentage of the bodyburnt and the main injuries are shown in the Table.A fuller description of the clinical, bacteriologicaland biochemical details will be presented elsewhere.'A brief clinical summary is given here.

All the men admitted to hospital developedbacterial infections. It is significant that one case hadKlebsiella aerogenes isolated from the throat onadmission. All cases had one or all the followingorganisms isolated from the blood during treatment:Klebsiella aerogenes, Proteus mirabilis, Acinetobacteranitretum, Pseudomonas pyocyanea, Pseudomonasaeruginosa and two strains of Staphylococcus aureus,one genatamicin-sensitive, the other gentamicin-resistant.The blood urea was raised in all but one case (case

4) who died on day 3. One patient was haemodialysedthree times. The platelet count was reduced in allpatients. It was below 100 x 109/l in six patients andin one patient fell to below 15 x 109/l. All the menneeded platelet infusions and received steroids.

All patients were mechanically ventilated. Theinspired oxygen was 30-100%. The percentage ofinspired oxygen in four patients is shown in Fig. 1.

1147

copyright. on D

ecember 23, 2020 by guest. P

rotected byhttp://jcp.bm

j.com/

J Clin P

athol: first published as 10.1136/jcp.34.10.1147 on 1 October 1981. D

ownloaded from

Details of cases and injuries sustained

Case no Age Percentage Fractures Other irijuries Day of deathburns (after explosion)

I 37 85 # ribs Deep laceration left leg FD2 41 70 # dislocation Pulmonary tear FD

left shoulder Laceration of pulmonary trunk# ribs Haemopericardium

3 29 87 Depressed # Subdural haematoma FDpost fossa Laceration of dura

Laceration of both lower lobes4 44 85 # patella Cerebral oedema 3

Gastric erosionsPulmonary tear

5 40 70 - Laryngeal oedema 4Acute tracheobronchitis

6 23 90 Supracondylar Subdural haemorrhage 644 humerus Tracheobronchitis4 ribs

7 41 85 - 88 36 70 - Tracheobronchitis 8

Myocardial abscesses9 44 45 _ Tracheobronchitis 13

Pancreatitis10 33 60 44 patella Laryngotracheobronchitis 13

Cerebral oedema

FD -found dead.

100 -

90

80

0

x

-oD 60-L-

-C

50

40

30

Fig. 1

treated i

PATHO

The casdead doeach ca

each loand ela;

# = fracture(d).

Menfound deadThree men were found dead in the mine. All three

5 cases had fractures. In one case there was laceration,-'-- -*. of the pulmonary trunk with a haemopericardium.

"6'86\ ,^ ' Macroscopically there was carbon pigment in thetrachea and bronchial tree. In all cases there was

'-\'-__,o'^"_,8" evidence of marked congestion in one or both lobes__' \ .~t of each lung. Two cases (cases 2 and 3) showed

9 lacerations of the lungs. Case I showed a finenodularity over the right lower lobe and some

/\/w\ \ silicotic nodularity in the left upper lobe.\/\\'__t Histologically one case (case 1) showed minimal

10 V focal intra-alveolar oedema. In case 2 there wasmarrow and fat embolism in the muscular pul-monary arteries and pulmonary arterioles, someinterstitial and intra-alveolar oedema as well ascongestion of the alveolar wall. In some alveolarspaces there was green material, most probably bile,indicating aspiration of gastric contents. An interest-ing finding in case 2 was the presence of clumps of

Days468 10 2 micro-organisms in some alveolar spaces as well as in

Days the alveolar capillaries and muscular pulmonaryLevel of inspired oxygen in four of the cases arteries (Fig. 2). The last case found dead (case 3)in hospital. had a pleural tear and also showed congestion of the

alveolar wall with proliferation of the alveolarcapillaries (Fig. 3) which extended into the alveolarlumina. There was pulmonary oedema and intra-

OLOGICAL FINDINGS alveolar haemorrhage which was most prominent inses can be split into two groups, those found the upper lobes.)wn themine and thosewho died in hospital. In Incidental findings unrelated to the explosion werevse two blocks of lung tissue were taken from centrilobular emphysema and small foci of fibrosis,be and stained with haematoxylin and eosin associated with carbon pigment. The mucousstic van Gieson. glands of the main bronchus showed hyperplasia.

Hasleton, Penna, Torry1148

copyright. on D

ecember 23, 2020 by guest. P

rotected byhttp://jcp.bm

j.com/

J Clin P

athol: first published as 10.1136/jcp.34.10.1147 on 1 October 1981. D

ownloaded from

Effect ofoxygen on the lungs after blast iniury and burns

...........

Fig. 2 Micro-organisms in pulmonary capillaries(case 2). Haematoxylin and eosin x 400.

Men transferred to hospitalThe changes in these seven cases can be classed inseveral pathological groups.

(1) InfectionAll of the cases showed evidence of consolidationwhich involved, in most cases, every lobe. In twocases (cases 8 and 9) there was macroscopic evidenceof multiple lung abscesses. Case 8 also showedulceration of the mucous membrane in the bronchialtree.

(2) Disseminated intravascular coagulationThis was regarded as being present when giantendothelial cells were seen (Fig. 4). These cells werepresent in all but one case (case 7). In three cases(cases 7, 8 and 10) there was evidence of micro-thrombi in pulmonary arteries and capillaries (Fig.5). Hyaline membranes (Fig. 6) were present in threecases (cases 6, 9 and 10) but were most pronouncedin case 9.

(3) Changes in the alveolar wall and alveolar lumenProminent interstitial oedema was present in 4 cases(cases 7, 8-10). Intra-alveolar oedema and haemor-rhage were present in all cases. Marked congestion ofthe alveolar wall was also seen in all cases. In threecases (cases 7, 9 and 10) cuboidal epithelium linedthe alveolar wall (Fig. 7) and in one case these cellsformed a syncytium in the alveolar lumen. It is mostlikely that these cells were type II pneumocytes

FFig 3 Proliferation of alveolar* -~~~ capillaries (arrowed) (case 3). Foot's

reticulin x 640.

1149

copyright. on D

ecember 23, 2020 by guest. P

rotected byhttp://jcp.bm

j.com/

J Clin P

athol: first published as 10.1136/jcp.34.10.1147 on 1 October 1981. D

ownloaded from

Hasletola, Penntia, Torry

;2. #t ... . s0***c

*4~..>.a.4

i,J-:'_

Fig. 5 Microthroanbus in muscular pulmionary artery(case 7). Haematoxylin and eosin x 640.

though with light microscopy it is not possible todifferentiate these cells from alveolar macrophages.

(4) Pulmonary fibrosisIn two cases there were foci of old pulmonaryfibrosis in the form of nodules with associated carbonpigmentation. Only one case (case 9) showed anyrecent fibrosis. This was detected in the hilar regionof the lung macroscopically and histologically wasseen focally in both upper lobes and the right middlelobe. The fibrosis was predominantly intra-alveolar(Fig. 7) though in the right upper lobe there was alsointerstitial fibrosis (Fig. 8). In some alveoli there wasalso intra-alveolar fibrin. Hyaline membranes wereassociated with the fibrosis as was the presence ofcuboidal cells lining the alveolar wall.

Fig. 4 Giant endothelial cells(arrowed) (case 10).Haematoxylin and eosin x 400.

1:4, *w .4.j 7

*t:.% w A^0. wts g ... :~'. aii9,kt . 4.....-¾

*fX..>..x,.., ..|..ffig Bg "N X b . S .j.. i~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~........A. s- S

A

Fig. 6 Iiyaline membrane (arrowed) involving alveolarduct and alveolus (case 9). Haematoxylin and eosinx 356.

(5) Otherpulmonary changesEvidence of pulmonary infarction was seen in onecase (case 8). In case 4 there was a laceration of theapex of the left lower lobe. Focal emphysema waspresent in two cases (4 and 9) and alveolar ductemphysema in two cases (6 and 8).One case (case 5) showed focal granulomata in the

alveolar wall. These showed no caseation andneither tubercle bacilli or fungi could be demon-strated. A diagnosis of early sarcoidosis was made.

Discussion

The present paper describes the pulmonary changes

llSO

--.;o: "Ik

copyright. on D

ecember 23, 2020 by guest. P

rotected byhttp://jcp.bm

j.com/

J Clin P

athol: first published as 10.1136/jcp.34.10.1147 on 1 October 1981. D

ownloaded from

Effect of oxygen on the lungs after blast injury and burns

Fig. 7 Intra-alveolar fibrosis alongwith some cuboidal epithelial cells(case 9). Haematoxylin and eosinx 256.

|s ./........

Fig. 8 Interstitialfibrosis (arrow) alongwith intra-alveolarfibrosis (case 9).Haematoxylin and eosinx 400.

in a series of ten men who were exposed to severeblast injury and suffered extensive burns. The mostimportant feature in the present study is a negativeone, the lack of pulmonary fibrosis. Only one case(case 9) had evidence of pulmonary fibrosis whichwas both interstitial and intra-alveolar. It is interest-ing to note that the inspired oxygen concentrationrequired by this patient decreased just before death,associated with treatment of his renal failure by

haemodialysis. The dialysis presumably removedsome of the pulmonary oedema. Had the fibrosisbeen severe and progressive, as might be expected inoxygen toxicity, then the inspired oxygen concentra-tion should have increased.Pulmonary fibrosis may not be the only criterion

of pulmonary oxygen toxicity. Sevitt2 gave thecriteria of hyaline membranes and proliferativepneumonitis as specific features of oxygen toxicity.

1151

..:.;:, .:. 4,.:

AAMA'am::::

.,.. :-.1

copyright. on D

ecember 23, 2020 by guest. P

rotected byhttp://jcp.bm

j.com/

J Clin P

athol: first published as 10.1136/jcp.34.10.1147 on 1 October 1981. D

ownloaded from

Hasleton, Penna, Terry

He found intra-alveolar fibrosis as early as 21 daysafter oxygen therapy though it appeared to be wellestablished by 5 days. Hyaline membranes werepresent in only three of the present series (cases 6, 9and 10). These cases had oxygen for 6, 13 and 13 daysrespectively. In the cases without hyaline membranesthe duration of oxygen therapy was 1 "-8 days.Hyaline membranes are not regarded as specificfor oxygen toxicity by all authors.3 6 Bachofen andWeibel7 studied seven patients, three in detail. Therewas one case of pancreatitis, a case of pulmonaryoedema following a fracture, complicated bybronchopneumonia and a case with multiplefractures. All patients were mechanically ventilated.One required an inspired oxygen concentration of75 %. In the other two patients the inspired oxygenwas kept below 45 %. Hyaline membranes were foundin these three cases. The authors state that hyalinemembranes are also present in the lungs of patientsdying of respiratory distress due to other causes; fatembolism, drowning, viral pneumonia and sepsis.Other changes found were irregular widening of theinterstitium due to oedema, fibrosis and increasedcellularity and metaplasia of the alveolar lining cellsinto a cuboidal epithelium. These appearances werenot thought to be due to oxygen toxicity since aninspiratory oxygen concentration of 400% is nottoxic to man or animals. Other authors8 9 haveemphasised that many of the changes of oxygentoxicity are non-specific.

Pratt10 noted capillary proliferation as an earlysign of oxygen therapy. However, we found capillaryproliferation in one of the miners found dead andhave seen it in burns cases not treated with oxygenand after myocardial infarction. Thus, as with theother histological features of oxygen therapy,proliferation of capillaries is an unreliable sign ofoxygen toxicity. It is possible from Pratt's descriptionthat some of his cases may have had disseminatedintravascular coagulation since he notes the presenceof endothelial cells which are "usually rather large."Pulmonary function studies have not helped to

elucidate the problem of oxygen toxicity. Caldwelland Weibel" thought that pulmonary oxygentoxicity develops in any person breathing oxygen(Po2 > 700 torr) for longer than 6 h. They do,however, say that oxygen toxicity is likely to occur inthe patient with respiratory failure from some othercause and there is no way, in such patients, of assess-ing the contribution oxygen plays in the respiratoryfailure. Barber et al'2 in a careful study investigated10 patients with irreversible brain damage. Half thepatients were ventilated with air and the rest with1000% oxygen. The first group were treated for amean of 104 h (range 50-216 h) and the oxygen groupfor a mean of 52 h (range 31-72 h). The oxygen group

showed a decrease in arterial oxygen tension and theintrapulmonary shunt and ratio of dead space totidal volume increased. These findings suggested thedevelopment of large areas of perfused but unventi-lated lung. Histology of the lung, however, wassimilar in both groups and hyaline membranes wereabsent in both groups. The elevation of the ratio ofdead space to tidal volume could possibly beexplained by the presence of disseminated intra-vascular coagulation (DIC).

In the same issue of the New England Journal ofMedicine, Singer et al" studied the effect of artificialventilation with pure oxygen for up to seven days inpatients after cardiac surgery. Though such patientsare likely to have abnormal pulmonary vasculatureand alveolar walls due to the underlying cardiacdisease these authors found no difference in the intra-pulmonary shunt, effective compliance, the ratio ofdead space to tidal volume or clinical course whencompared with controls. One case had oxygen forfive days and recovered uneventfully. Another casedied on the seventh day from intrapulmonaryhaemorrhage due to anticoagulants. This case didhave early interstitial fibrosis and hyaline mem-branes. However, in the presence of congestivecardiac failure and pulmonary haemorrhage theirsignificance is difficult to interpret. Van De Water etal14 showed no changes in the alveolar/arterialoxygen gradient, pulmonary artery pressure orpulmonary resistance in a group of healthy youngmen exposed to oxygen for 6 to 12 h. Comroe et a115did a similar experiment for 24 h and with 500%oxygen produced no ill effects in the men studied.Astronauts can tolerate several weeks of pureoxygen at one third atmospheric pressure withoutshowing any significant impairment of pulmonarygas exchange.

In one clinical study of blast lung16 two womendeveloped pulmonary oedema. One of the patientsreceived 100% oxygen for at least 25 days but thepulmonary changes apparently resolved and thepatient was able to leave hospital. It has beenpostulated that it is the arterial oxygen tension whichis of more significance than the inspired oxygenconcentration. There is some experimental proof forthis17 in that initial changes of oxygen toxicity in ratsoccur in endothelial cells.We shall not deal with the experimental evidence

in favour of oxygen toxicity as this has already beensummarised.6 However, as these authors state thereis interspecies variation in the oxygen susceptibilityof the various alveolar cells and small animals aremore susceptible to oxygen than large animals suchas monkeys. It is still a big jump to equate thechanges in monkeys' lungs due to oxygen with thosein humans.

1152

copyright. on D

ecember 23, 2020 by guest. P

rotected byhttp://jcp.bm

j.com/

J Clin P

athol: first published as 10.1136/jcp.34.10.1147 on 1 October 1981. D

ownloaded from

Effect of oxygen on the lungs after blast injury and burns

The present study suggests that oxygen may not beas toxic, certainly over a period of 13 days, as hasbeen previously suggested. In a sufficiently highconcentration over a prolonged period of timeoxygen may harm the lung but in the short term,based on the present study, if the patient's conditionrequires it, high inspired oxygen should be admini-stered. The concentration of inspired oxygenrequired by the one case, with some focal pulmonaryfibrosis, decreased before death probably due tohaemodialysis. If a progressive fibrosing alveolitishad been occurring we would have expected anincreased oxygen requirement. Any patient onoxygen is usually receiving it because there is someunderlying pulmonary damage due, for example, toshock, trauma, fat embolism or disseminated intra-vascular coagulation. It may be that any of theseprocesses render the lung more vulnerable to theeffects of oxygen. In this study the lungs from theminers found dead were abnormal; there waspulmonary oedema, fat and marrow embolism andsome interstitial oedema. Thus it is probable thatthere was underlying damage to the alveolar wall,due to the explosion.

It appeared that there were two distinct phases inthe pulmonary changes as shown by the presentseries. In the three patients found dead there wasintra-alveolar haemorrhage, oedema, interstitialoedema and, in one case, fat and marrow embolism.Such changes can be seen in animals exposed to blastinjury.18 Similarchanges, apart from the fat embolism,are present in patients with burns who have notreceived oxygen. It is interesting that in a shortreview of shock lung,19 Beyer describes in somecases, microthrombi and hyaline membranes. Thesewere not present in our cases in the early stages ofshock lung. It appears that the first changes in thelung after shock are vascular, probably because of alack of nutrient flow.5 20 21 As a consequence of thisthere is increased permeability of the basementmembranes which will give rise to intra-alveolar andinterstitial oedema. Surfactant production is re-duced. Both endothelial and alveolar cells aredamaged and this may lead to hyaline membraneformation.The presence of intra-alveolar oedema, focal

atelectasis and lack of pulmonary surfactant as wellas extensive burns sets the scene for pneumoniawhich was present in all cases who died in hospital. Itis interesting that in one of the patients found dead,organisms were present in the lung. These were car-ried in the pulmonary vasculature though we cannotentirely rule out a primary colonisation of the lung.It is interesting that a Klebsiella was grown from athroat swab taken on admission from one of theminers sent to hospital.

Associated with the infection, or perhaps pre-ceding it, was evidence of disseminated intra-vascular coagulation. This is manifest by the for-mation of globular hyaline microthrombi and giantendothelial cells. These latter cells are regarded bysome authors2'22 as megakaryocytes. The formerauthors rarely found these cells in the spleen, liverand kidney. There was a significant correlation withthe presence of such cells and intravascular coagu-lation in cases dying of acute infections, cirrhosis,cancer and shock. It should be noted that "mega-karyocytes" though found in control cases arepresent in smaller numbers. The Aberdeen group23regard these cells, both on light and electronmicroscopy, as endothelial cell nuclei and notmegakaryocytes. They give them the name "haema-toxylinophil bodies." Support for the endothelial cellorigin comes from rabbits given Escherichia coliendotoxin.24 In these animals large numbers ofendothelial cells were seen in the blood withinminutes of injection of low doses of endotoxin.

We wish to thank Mr DP Blakey, HM Coroner forGreater Manchester County (West) for permission toreport these cases.

References

Penna P, Hey V, Orton C, Hasleton PS. 1981; In pre-paration.

2 Sevitt S. Diffuse and focal oxygen pneumonitis; a pre-liminary report on the threshold of oxygen toxicity inman. J Clin Pathol 1974;27:21-30.

3 Martin AM Jr, Soloway HB, Simmons RL. Pathologicanatomy of the lungs following shock and trauma.J Trauma 1968;8:687-98.

4 Bredenberg CE, James PM, Collins J, Anderson RW,Martin AM Jr, Hardaway RM. Respiratory failure inshock. Ann Surg 1969;169:392-403.

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

Katzenstein A-LA, Bloor CM, Leibow AA. Diffusealveolar damage-the role of oxygen, shock and relatedfactors: a review. Am JPathol 1976;85:210-28.

Bachofen M, Weibel ER. Basic pattern of tissue repair inhuman lungs following unspecific injury. Chest suppl1974;65:14S-9S.

8 Deneke SM, Fanburg BL. Normobaric oxygen toxicity ofthe lung. N Engl J Med 1980;303:76-86.

9 Wolfe WG, DeVries WC. Oxygen toxicity. Annu Rev Med1975;26:203-17.

10 Pratt PC. Pulmonary capillary proliferation induced byoxygen inhalation. Am J Pathol 1958;34:1033-49.

Caldwell PRB, Weibel ER. In: Fishman AP, ed. Pulmonaryoxygen toxicity in pulmonary diseases and disorders. NewYork: McGraw Hill, 1980;800-5.

12 Barber RE, Lee J, Hamilton WK. Oxygen toxicity in man;a prospective study in patients with irreversible braindamage. N EngilJ Med 1970;283:1478-84.

13 Singer MM, Wright F, Stanley LK, Roe BB, HamiltonWK. Oxygen toxicity in man; a prospective study in pat-ients after open-heart surgery. NEnglJ Med 1970;283:1473-8.

1153

copyright. on D

ecember 23, 2020 by guest. P

rotected byhttp://jcp.bm

j.com/

J Clin P

athol: first published as 10.1136/jcp.34.10.1147 on 1 October 1981. D

ownloaded from

1154

14 Van De Water JM, Kagey KS, Miller IT et al. Response ofthe lung to six to 12 hours of 100% oxygen inhalation innormal man. N Engl J Med 1970;283:621-6.

15 Comroe JH Jr, Dripps RD, Dumke PR, Deming M.Oxygen toxicity: the effect of inhalation of high con-centrations of oxygen for twenty-four hours on normalmen at sea level and at a simulated altitude of 18 000feet. JAMA 1945;128:710-7.

16 McCaughey W, Coppel DL, Dundee JW. Blast injuries tothe lungs; a report of two cases. Anaesthesia 1973;28:2-9.

17 Kistler GS, Caldwell PRB, Weibel ER. Development offine structural damage to alveolar and capillary liningcells in oxygen-poisoned rat lungs. J Cell Biol 1967;32:605-28.

18 Zuckerman S. Experimental study of blast injuries to thelungs. Lancet 1940;ii:219-24.

'9 Beyer A. Shock lung. Br J Hosp Med 1979;21:248-59.20 Vieth FJ, Sinha SBP, Graves JS, Boley SJ, Dougherty JC.

Hasleton, Penna, Torry

Ischaemic tolerance of the lung. The effect of ventilationand inflation. J Thorac Cardiovasc Surg 1971 ;61 :804-10.

21 Corrin B. Lung pathology in septic shock. J Clin Pathol1980;33:891-4.

22 Aabo K, Hansen KB. Megakaryocytes in pulmonary bloodvessels. 1. Incidence at autopsy, clinico-pathologicalrelations especially to disseminated intravascularcoagulation. Acta Pathol Microbiol Scand [A] 1978;86:285-91.

23 Brown LT, Stalker AL, Hall J. Experimental defibrinationII Histological studies by light and electron microscopy.Microvasc Res 1969 ;1 :295-307.

24 Gaynor E, Bouvier CA, Spaet TH. Circulating endothelialcells in endotoxin treated rabbits. Clin Res 1968;16:535.

Requests for reprints to: Dr PS Hasleton, Department ofHistopathology, Withington Hospital, West Didsbury,Manchester M20 8LR, England.

copyright. on D

ecember 23, 2020 by guest. P

rotected byhttp://jcp.bm

j.com/

J Clin P

athol: first published as 10.1136/jcp.34.10.1147 on 1 October 1981. D

ownloaded from