bronchiolitis from nitrous fumes · case 1 is that of a man aged 24 years, who was employed as a...

Thlorax (1958), 13, 327.

BRONCHIOLITIS FROM NITROUS FUMES *BY

CHRISTOPHER S. DARKE AND A. J. N. WARRACKFrom the City General Hospital, Sheffield

The inhalation of noxious fumes causes damageto the air passages and alveolar walls. Theresponse covers a wide range, depending upon thenature of the gas, its concentration in the lungs,and the duration of exposure. Certain irritantgases, notably chlorine and ammonia, have animmediate effect on the upper respiratory tract,with intense burning in the throat, choking, andattacks of laryngeal spasm. Other gases whichinclude nitrous fumes exert a less violent reactionat first but are commonly followed by an acutepulmonary oedema and bronchiolitis. This maybe due to the fact that their relative insolubilityin water allows deeper penetration of thebronchial tree.The purpose of this paper is to describe two

cases of acute bronchiolitis, following the inhala-tion of nitrous fumes, that were observed inSheffield in 1956. One patient died.

CASE REPORTSCase 1 is that of a man aged 24 years, who was

employed as a steel wire cleaner. He had fair healthbut from an early age had suffered from mild attacksof recurrent bronchitis. This had not caused muchincapacity and had never been investigated. Theaccident occurred on April 4, 1956. He was carryingnitric acid in a rubber bucket when he found that ithad sprung a leak. He held the rubber bucket overanother bucket of galvanized iron to receive the spil-lage and the immediate chemical reaction betweenthe acid and metal produced reddish-brown fumes ofnitrogen dioxide. It was alleged that he was exposedto the fumes for about 30 seconds. Immediately afterthe incident he said that he felt no ill effects and hecompleted his shift before returning home in theearly afternoon, when he first complained of feelingunwell. His symptoms consisted of a distressingcough and the production of some mucoid, frothysputum. He remained at home for five days and thenreturned to work for one day. He found he couldnot continue and his doctor was first called onApril 11, a week after the actual exposure. A diag-nosis of bronchitis was made and he was kept in bedat home until he was admitted to hospital in a mori-

*Based on a paper read to the Thoracic Society in Newcastle inJuly, 1957.

bund condition on April 18. A thorough examina-tion was then impossible, but the clinical picture wasone of extreme cyanosis, dyspnoea, and fine rales overthe lungs. He was thought to have extensive bron-chopneumonia and this appeared to be confirmed bya radiograph which showed soft, discrete opacitiesthroughout the whole of both lung fields with theexception of the right lower lobe (Fig. 1). He sur-vived only a few hours.NECROPsY.-The examination was made seven hours

after death. The body was that of a young adultmale of average nutrition. There was no externalevidence of disease and no blistering around or with-in the mouth. The significant findings were confinedto the thoracic contents. The larynx showed moder-ate oedema. The tracheal and bronchial mucosa wascongested and there was patchy superficial desquama-tion. The bronchi of both lungs were filled withthick mucopus. Both pleural sacs showed chronicadhesions. The whole of the left lung and the upperand middle lobes of the right lung showed averageanthracotic pigmentation for a resident in an indus-trial area. They were consolidated and on section

FIG. l.-Case 1. Chest radiograph taken a few hours before deathshowing discrete opacities throughout the left lung and the rightupper lobe.

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328CHRISTOPHER S. DARKE and A. J. N. WARRACK

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FIG. 2.-Case 2. Chest radiograph on April 11, 1956, showing softopacities throughout both lungs.

showed widespread small, yellow areas, having theappearance of a generalized bronchiolitis. The rightlower lobe was completely free of carbon pigmentand of a different texture. It was relatively airlessand on section showed extensive chronic cystic bron-chiectasis. This was evidently of long duration andunconnected with death. The cardiovascular systemwas normal apart from terminal right ventriculardilatation. The oesophagus showed a little desqua-mation of the epithelium, but the remainder of thealimentary tract was normal. Other internal organs,including the brain, were normal.

Microscopical examination of the left lung and theupper and middle lobes of the right lung showed an

extensive organizing bronchiolitis, characterized bymiliary collections of fibroblasts, plasma cells, andlymphocytes in the centre of which were remnants ofbronchioles and bronchiolar epithelium (Figs. 4and 5). In some areas there was a localized alveolarreaction, the spaces being filled with a polymorpho-nuclear exudate (Fig. 6), whilst in others the bron-chioles were less affected and showed only epithelialdesquamation (Figs. 7 and 8). There was no evidenceof tuberculosis. An oesophageal ulcer showed mini-mal round cell infiltration. The liver and kidneyswere normal. The appearances were consistent witha diagnosis of obliterative bronchiolitis in an earlystage of organization and resembled that which isknown to follow the inhalation of nitrous fumes.Case 2 is that of an electroplater aged 59 years,

who was admitted to hospital on April 10, 1956, 17days after the inhalation of nitrous fumes.

FIG. 3.-Case 2. Chest radiograph on May 2, 1956, showing a linearand reticular appearance.

Since the age of 19 he had developed an electro-plating business. He worked with chrome and nickeland in later years cadmium had also been used. Hewas fully aware of the occupational hazards and hadseen that precautions were taken whenever there wasa risk of inhaling poisonous fumes. Both he and hisworkmen wore protective masks on these occasions.He was proud of his health and had never sufferedany significant respiratory illness. For this reason aprevious physical examination and chest radiographhad not been made.On March 16 he suffered from a mild upper respi-

ratory tract infection which took a week to subside.On March 22 and 23 he stripped 22,000 cadmium-

lined bolts. On the first day he placed about 200 ofthese bolts in wire baskets and subsequently dippedthem in a mixture of nitric acid one part and sul-phuric acid four parts. In this process a reddish-brown gas was given off. About 8,000 bolts weretreated in this manner. On the second day he re-peated the process with the remaining 14,000 bolts,but used a weaker solution of nitric acid alone.During these procedures, which were carried out in

the yard, he did not wear a mask and relied entirelyon the gases being carried away in the atmosphere.He admitted that he must have inhaled a considerablequantity of the brown vapour. There was no imme-diate distress, but during the remainder of the week hedid not feel well, putting this down to the after-effects of his cold.

Seven days after exposure, on the night ofMarch 30, his voice became husky and his chest felt

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BRONCHIOLITIS FROM NITROUS FUMES

Fio. 4.-Case 1. Minute foci of obliterative bronchiolitis wi.haassociated alveolar reaction. Haematoxylin and eosin. x 5.

tight. His lips and throat were burning and he feltas though he were on fire. An uncontrollable par-oxysmal cough developed, and he expectorated a con-siderable amount of frothy mucus which was fre-quently streaked with blood. He became feverishand restless with great physical and mental distressfrom incessant spasms of coughing and from intensedyspnoea. Marked cyanosis developed. He receivedfive daily injections of 600,000 units of procaine peni-cillin. At no time did his sputum become purulent.When first seen in hospital, he was afebrile,

cyanosed, and distressed by explosive bouts of awheezy and mostly unproductive cough. Clinicalexamination revealed a deep chest with weak breathsounds at the bases. Inspiratory rales were audibleover both lungs. The cardiovascular and othersystems were normal.A diagnosis of bronchiolitis was made and a chest

radiograph on April 11 (Fig. 2) showed soft, irregularopacities throughout both lungs with a suggestion ofbullous changes or abscess formation in a few areas.He had a mild fever for three days and was treatedwith chlortetracycline, 2 g. daily, for five days, reduc-ing to 1 g. for a further seven days. His cyanosislessened rapidly, and by the end of the first week inhospital the breath sounds over the lower lobes

became normal, although he remained dyspnoeic onthe slightest exertion.With the purpose of limiting the scarring process,

cortisone was also given in a dosage of 150 mg. onthe first day, then 100 mg. daily for five days,followed by gradual withdrawal over the ensuingeight days.

INVESTIGATIONS.-Culture of the sputum yielded amixed bacterial growth and repeated examinationsfailed to demonstrate tubercle bacilli.The leucocyte count was 14,000 per c.mm., of

which 84% were polymorphonuclear neutrophils.The sedimentation rate (Westergren) was 55 mm. inone hour. An electrocardiogram was normal. Sero-logical tests for infection by the influenza and thepsittacosis-L.G.V. groups of viruses, by the adeno-viruses, and by R. burneti were all negative on the29th day of illness, as was that for agglutination ofstreptococcus MG.A second chest radiograph taken one week after

admission showed no material change, but subsequentradiographs (Fig. 3) showed progressive clearing ofthe soft opacities from both lungs but left a finelinear and reticular pattern suggesting an interstitialfibrosis.

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FIG. 5.-Case 1. Miliary focus showing bronchiolar desquamationand surrounding roaction. Haematoxylin and eosin. x 5.

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FIG. 8.-Case 1. Early bronchiolar desquamation. Haematoxylin and eosin. x 45.

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Despite this, the clinical course was satisfactoryand he was discharged from hospital after 14 daysand has made a complete recovery. A radiographeight months later was normal.

DISCUSSIONTHE OXIDES OF NITROGEN.-The oxides of

nitrogen are nitrous oxide (N20), nitrogentrioxide (N203), nitrogen pentoxide (N,05), nitricoxide (NO), and two forms of nitrogen dioxide(NO2 and N204). Gray, Goldberg, and Patton(1954) carried out a series of animal experimentswhich demonstrated the toxic effects of nitrogendioxide.

Nitric oxide is a colourless, non-irritating gas

which undergoes comparatively rapid oxidation inair to nitrogen dioxide. At body temperature thedioxide exists as a reddish brown vapour consist-ing of approximately 30% of NO2 and 70% ofN,04.

Nitrogen dioxide is a moderate irritant and isrelatively insoluble in water as compared withchlorine. It may be inhaled into the deeper partsof the lungs where it will react with the water ofthe respiratory membrane to form nitric andnitrous acids which cause the lesion.

INDUSTRIAL HAZARDS.-Dangerous concentra-tions of nitrous fumes may arise from the use

of nitric acid in a variety of commercial processes,particularly when work is carried out in confinedand ill-ventilated spaces.

Nitric acid is used in the dipping of copper,silver, and brass articles and in the manufactureof toluene, metallic nitrates, methyl nitrate, cellu-lose, nitrocellulose, collodion, and prussian red; inengraving, in the testing of metals, and in the manu-facture of certain jewellery and artificial leather;in the commercial production of sulphuric, picric,and chromic acids; and with other acids indescaling and pickling plants for stripping steelsheets after firing and rolling. In these and otherprocesses, irritant fumes are created which mayreach a dangerous level if there is inadequateventilation.

Nitrous fumes may also be liberated from theslow burning or incomplete detonation of nitro-explosives. Many men employed in gun turretsduring the two world wars were exposed to a highconcentration of these gases, with disastrousresults. Occasional cases of poisoning have beenreported in the mining and tunnelling industries(Henry, 1939), although fortunately the risk isvery small in coal-mines where ventilation is satis-factory. A number of deaths have been notifiedin the deep gold-mines of India and the Transvaal

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(Hunter, 1955). In these instances it is clear thatthe overriding factor has been poor ventilation.The most comprehensive description of lung

damage from nitrous fumes is that of Nichols(1930). This was based upon experience of adisaster which followed the slow burning of vastquantities of nitrocellulose films in a hospital inCleveland, Ohio. There were 110 deaths.A potential danger also exists during work with

the electric arc. Welding at the high tempera-tures created by the arc gives rise to numerousgases. It is generally conceded that the ill effectsof inhalation of such fumes can be ascribedwholly or in part to the oxides of nitrogen(Tollman, MacQuiddy, and Schonberger, 1941;La Towsky, MacQuiddy, and Tollman, 1941).Camiel and Berkan (1944) described the case

of a worker who, without a protective mask, wasexposed to a high concentration of fumes for aperiod of four and a half hours while assisting anacetylene welder in the brazing of pipes. Theyworked in a ship's hold where ventilation waspoor. The man continued at work for a furtherfour and a half hours before complaining of dizzi-ness, coughing, and difficulty in getting his breath.Cases of fatal gas poisoning in acetylene weldinghave been recorded by Koelbel (1938), Maenicke(1937), Mawich (1938), and Williman (1935).At the present time, nitric acid is used as an

oxidizer in rocket fuel, so that an occasional caseof poisoning may be expected from this source.

CLINICAL FEATURES.-The initial symptomsvary with the concentration of the gas and theduration of the exposure. Inhalation of a lowconcentration of nitrogen dioxide provokes mildirritation of the eyes and throat, a dry cough, andtightness of the chest. Occasionally dizziness,nausea, or vomiting may occur. Often a man maycontinue to work in the contaminated atmosphere,as the appreciation of irritation soon becomesdulled. In that event, irreparable damage to thealveolar epithelium occurs, often without thepatient being aware of the dangerous situation.The acute suffocative distress which immediatelyfollows inhalation of chlorine or ammonia is notseen with nitrous fumes.

Nitrogen dioxide in high concentrations, par-ticularly in confined spaces, causes greater dis-comfort, which rapidly diminishes when the manbreathes fresh air. After cessation of exposure,there may be a latent interval of many hoursbefore further symptoms occur. These take theform of increasing dyspnoea and cyanosis,paroxysmal cough and expectoration of frothysputum. The clinical picture is that of bronchi-

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CHRISTOPHER S. DARKE and A. J. N. WARRACK

olitis. Auscultation of the lungs at this phasereveals generalized medium and fine rales.

Mild cases recover after a few days of acuterespiratory distress. At any time, secondaryinfection may occur when the retained secretionscause scattered areas of atelectasis and pneumonia.Appropriate treatment may save the patient's life,although recovery is often delayed for manyweeks. Severe poisoning causes death fromacute pulmonary oedema. Peripheral circulatorycollapse rapidly supervenes and at this stageneither oxygen nor measures to combat the stateof shock are of any avail.

RADIOGRAPHIC APPEARANCES.-The radiographicchanges are in no way diagnostic. In thefulminant case, the patient is usually too ill forchest radiography. Such records as are availablereveal the features of acute pulmonary oedema.The shadows clear rapidly if the patient survives.

Less severe exposure is followed after a shortinterval by irregular soft, mottled shadowsthroughout the lungs (Camiel and Berkan, 1944).The shadows vary in size from 2 to 10 mm. indiameter and may be interpreted as small areas ofcollapse or pneumonia. Some of these opacitiesmay become confluent. With effective therapy,rapid resolution of these changes may be expected.

Nichols (1930), Doub (1933), Holland (1937),and Henry (1939) have each described the radio-logical appearance resulting from acute exposureto nitrogen dioxide and have emphasized thatcomplete resolution is the rule.TREATMENT.-Immediate removal from the

dangerous area is the first consideration.Absolute rest must be imposed for at least 24hours after exposure, and it is advisable for thepatient to be admitted to hospital forthwith(McNally, 1942). At the onset of dyspnoeaoxygen should be administered by any methodensuring full oxygenation. It has been suggestedthat positive pressure respiration may have a placein the treatment of pulmonary oedema (Hardyand Barach, 1945). At the same time, antibioticsare needed in full dosage to prevent the seriousconsequences of secondary infection.PATHoLoGY.-Nitrous fumes exert a corrosive

action upon the respiratory mucous membrane.Since breathing may proceed without unduedistress, due to the relatively low solubility of thegases, the alveolar epithelium invariably sufferssevere damage. The naked-eye and histologicalappearances are those of acute pulmonaryoedema. The mucosal lining of the bronchiolesis also particularly vulnerable, and the membrane

may be shed in its entirety. Similar damage mayaffect the remainder of the tracheobronchial tree.Microscopical examination shows that the lumenof the smaller tubes is filled with detritus, con-sisting of desquamated epithelium, fibres, red cells,and leucocytes invaded by granulation tissue.The muscular and elastic fibres in the walls mayshow disruption or complete dissolution and thereis usually a surrounding alveolar reaction.Should the patient survive the initial onslaught,a patchy atelectasis or widespread broncho-pneumonia occurs, which apparently may healwith little or no scarring. Occasionally this acutenecrotizing bronchiolitis is followed by partial orcomplete obliteration of the lumen.

In that event, extreme respiratory distress ensues,leading to the clinical picture of bronchiolitisobliterans, as was evident in the first casedescribed in this report. Becklake, Goldman,Bosman, and Freed (1957) have described twopatients who suffered from dyspnoea some monthsafter exposure to nitrous fumes. They consideredthat the physiological disturbance might be ex-plained by narrowing of bronchial passages as asequel to acute bronchiolitis.

CONCLUSION.-There is usually no difficulty inmaking a correct diagnosis provided a history ofexposure is given. Most cases develop an acutepulmonary oedema due to the severe damage tothe alveolar walls. Very mild cases present as anacute, dry tracheo-bronchitis to which there are nosequels unless a virulent infection supervenes. Athird group comprises those patients who do notdevelop pulmonary oedema, but suffer from avariety of effects based upon an intense general-ized bronchiolitis. As a direct result of thecorrosive action of the vapour and of addedinfection the associated lobules become airless andinvaded by organisms. What amounts to a

chemical bronchopneumonia results. Case 2 ofthis report is representative of this group andillustrates that full recovery is possible, particu-larly if appropriate antibiotics are administered tomaster the secondary infection. On the otherhand, necrosis and shedding of the bronchiolarepithelium may be followed by an exuberantgranulation tissue and fibroblastic proliferation.These obliterative changes, which are illustrated inCase 1, are usually seen at the time of relapse,some 15 days after exposure.

Nichols (1930) described a group of victims inthe Cleveland disaster who showed a phase ofclinical improvement followed by a relapse andsevere cyanosis. Radiographs of the chest showed

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small nodules throughout the lungs. Histologic-ally these were described as foci of interstitialfibrosis, but it is quite as likely, as suggested byMcAdams (1955), that these were lesions ofbronchiolitis obliterans.

SUMMARYTwo patients are described who suffered from

bronchiolitis following the inhalation of nitrousfumes. In one instance, death occurred 14 daysafter exposure from a generalized obliterativebronchiolitis. The other patient recovered com-pletely after a period of intense dyspnoea andcyanosis.A brief account is given of some of the known

occupational hazards. In view of the extensiveuse of nitric acid in industry, it seems likely thataccidents will continue to occur.

We wish to thank H.M. Coroner, Sheffield, for per-mission to publish the details of Case 1, as well asDr. F. J. Flint for allowing us to report the clinical

features. Our thanks are also due to Dr. T. Lodge,Dr. D. W. Auchinachie, and Dr. A. Jordan for theirhelp and interest and to Mr. C. Lambourne for thephotomicrographs.

REFERENCES

Becklake, M. R., Goldman, H. I., Bosman, A. R., and Freed, C. C.(1957). Amer. Rev. Tubere., 76, 398.

Camiel, M. R., and Borkan, H. S. (1944). Radiology, 42, 175.Doub, H. P. (1933). Ibid., 21, 105.Gray, E. L., Goldberg, S. B., and Patton, F. M. (1954). A.M.A. Arch.

industr. Hyg., 10, 409.Hardy, G. C., and Barach, A. L. (1945). J. Amer. med. Ass., 128, 359.Henry, M. G. (1939). Industr. Med., 8, 477.Holland, G. (1937). Med. Klin., 33, 930.Hunter, D. (1955). The Diseases of Occupations. English Universities

Press, London.Koelbel, A. (1938). J. industr. Hyg., 20, 82 (abst.).La Towsky, L. W., MacQuiddy, E. L., and Tollman, J. P. (1941).

Ibid., 23, 129.McAdams, A. J. (1955). Amer. J. Med., 19, 314.McNally, W. D. (1942). Industr. Med., 11, 207.Maenicke, R. (1937). J. industr. Hyg., 19, 38 (abst.)Mawich, R. (1938). Ibid., 20, 16 (abst.).Nichols, B. H. (1930). Amer. J. Roentgenol., 23, 516.Tollman, J. P., MacQuiddy, E. L., and Schonberger, S. (1941).

J. industr. Hyg., 23, 269.Williman, F. L. (1935). Ibid., 17, 129.

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