of bronchiolitis obliterans. The patient ... least two patients with bronchiolitis obliterans relapse occurred ... In the case of children, one tablet of. Slow-Fe daily is a ...
Silofiller's disease JOHN A. FLEETHAM, MB, FRCP[C]; PETER W. MUNT, MD, FRCP[C]; BRIAN W. TUNNICLIFFE, MD
Pulmonary disease following exposure to silage gas is one of the risks of the inhalation of oxides of nitrogen. These gases have also been incriminated as a cause of respiratory disorders following the inhalation of fumes from slow-burning nitrocellulose roentgenographic film,1 the use of acetylene welders in confined spaces,2 the detonation of certain explosives3 and accidents involving nitric acid.4 Despite the fact that the risks of entering a recently filled silo have been known for many years,5 persons with silo-filler's disease - a preventable disorder continue to be seen. We report a further two incidents, involving four men, to increase the awareness of this continuing occupational hazard. Case reports Incident 1 In mid-September 1977 three previously healthy men aged 31, 33 and 47 years died after entering a silo that had been filled with corn the previous day. The growing season had initially been dry and later very wet, and the soil had been especially well fertilized; as a result the corn grew exuberantly just prior to an early harvest. The first man entered the 7 x 21-in concrete silo (Fig. 1) to level the unevenly distributed corn without having run the blower fan beforehand. The other two men entered the silo a halfhour later when the first did not reappear; the collapse of one of the From the department of medicine, Queen's University, Kingston Reprint requests to: Dr. Peter W. Munt, Department of medicine, Queen s University, Kingston, Ont. K7L 3N6
former was seen to occur within 20 to 30 seconds by a hired hand who had climbed the inside ladder and opened a door into the silo. Later an ambulance attendant at the scene noticed a pungent odour, but satisfactory gas samples were not obtained because of the rescue attempts. Autopsy of one of the men showed early hemorrhagic pulmonary edema. In postmortem blood samples methemoglobin accounted for 44%, 38% and 38%, respectively, of the total hemoglobin content. incident 2 A 27-year-old nonsmoking farmer was admitted to hospital with progressive dyspnea. Two months previously he had felt nauseated and short of breath for 24 hours after entering a recently filled silo. Although he felt well for the next 2 to 3 weeks, he subsequently became progressively short of breath to the extent that he was unable to work.
FIG. 1-Plan of typical tower silo, 7 X 21 m, demonstrating abnormal distribution of corn in incident 1 of fatal silo-filler's disease.
482 CMA JOURNAL/SEPTEMBER 9, 1978/VOL 119
At the time of admission, physical examination of the chest revealed bilateral rales. A chest roentgenogram (Fig. 2) showed predominantly rightsided pulmonary interstitial infiltrates, and pulmonary function studies demonstrated a moderate obstructive and restrictive defect. Thermophilic precipitins were not detected in the serum. A specimen from an open lung biopsy (Fig. 3) showed changes characteristic of bronchiolitis obliterans. The patient was discharged taking corticosteroids. Three years later the man was asymptomatic and his chest roentgenogram was normal, but pulmonary function tests revealed a persistent mild obstructive defect and reduced diffusion capacity. Discussion The oxides of nitrogen, the gases responsible for silo-filler's disease, are derived from the nitrates within
silage, which are fermented into nitrites and oxygen. The nitrites combine with organic acids in the silage to form nitrous acid. As the temperature within the silo rises during fermentation the nitrous acid decomposes into water and a mixture of nitrogen oxides including nitric oxide, nitrogen dioxide, nitrogen trioxide, nitrogen tetroxide and nitrogen pentoxide.6 Nitrogen dioxide, which is reddish brown and has a pungent odour, is thought to be the principal agent responsible for the pulmonary injury. This process usually begins soon after ensiling and continues for at least 10 days. Drought, heavy fertilization of soil and crop immaturity all increase the nitrate content of plants and the subsequent production of these gases.7 Within the lung nitrogen dioxide reacts with water to form nitric acid, which causes extensive local damage. Pulmonary edema occurs when high concentrations of the gas are inhaled. With low concentrations an inflammatory exudate and bronchoconstriction are seen. The clinical presentation of silofiller's disease appears to depend on the intensity and duration of exposure to silage gas. Sudden death may occur when the individual enters the silo. Such was the case in incident 1, in three silo-related deaths in British Columbia (E.L. Anderson: personal communication, 1975) and in the four cases described in the original report of the disorder.' The collapse of one of the men in incident 1, seen to occur within 20 to 30 seconds of exposure to silage gas, was too sudden for pulmonary edema to have developed; this suggests that death was due to hypoxia. The oxides of nitrogen consume oxygen as they are produced; the result is gases that are heavier than oxygen. Thus oxygen is not only less available generally, but also is displaced from the silo base by the heavier nitrogen oxide and can cause severe methemoglobinemia. If the initial exposure to silage gas is survived, noncardiogenic pulmonary edema ifiay develop over the next 24 hours, causing cough, dyspnea, fever, bilateral pulmonary infiltrates and progressive hypoxemia - the characteristic features of adult respiratory distress. syndrome. This stage appears to be self-limiting, but controlled oxygen therapy and, when
necessary, mechanical ventilation should be given; the value of corticosteroid therapy is unclear. Severe methemoglobinemia should be treated with intravenous infusion of methylene blue.8 A latent period of several weeks or month follows, during which patients are relatively asymptomatic. The subsequent course may be that of the individual in incident 2, who had progressive dyspnea, pulmonary interstitial infiltrates with discrete nodularity, and a moderate obstructive and restrictive defect demonstrated by pulmonary function testing. Bronchiolitis obliterans is seen histologically during this stage.' It is difficult to make any objective assessment of the place of corticosteroids in the treatment of this condition because of the small number of reported cases. However, in at least two patients with bronchiolitis obliterans relapse occurred when corticosteroid therapy was discontinued.'0'11 The possibility that single or repeated episodes of exposure to silage gas may cause chronic pulmonary disease was raised more than 20 years ago.6 Repeated exposure to the oxides of nitrogen are probably common within the farming community, and significant exposure can occur outside at the base of a recently filled silo." While some patients appear to recover completely,6'7"3"4 some, as in incident 2, show various
degrees of impaired pulmonary function.""""7 The risk of chronic pulmonary disease cannot be evaluated on the basis of currently available data.'4 Since the farming community is a diffuse population prone to other respiratory disorders, such as hypersensitivity pneumonitis, only a detailed epidemiologic survey could evaluate this risk. Such a survey may be justified, for the frequency of this disease is likely to increase as the farming industry becomes more sophisticated. The present trends to fertilize soil heavily with nitrates and to build larger, more airtight silos are increasing the hazard of exposure to silage gas. The main responsibility for preventing this disorder and its consequent tragedies lies with the farmers. They are often far too casual in observing the recommended precautions, which were outlined more than 20 years ago:7 1. Allow no one to enter a silo from the time filling is begun until at least 2 weeks after it is finished. (Although gas production is complete by this time, the gases may remain in poorly ventilated silos for longer periods. Significant exposure has occurred at least 6 weeks after the completion of silo-filling.") 2. Always run the blower fan prior to entering the silo. 3. Do not enter a silo alone. 4. Provide fencing and good vent-
1" '
I
FIG. 3-Two bronchioles with intraluminal organized fibrous projections containing many acute and chronic inflammatory cells, changes characteristic of bronchiolitis obliterans (hematoxylin-eosin; X 50). CMA JOURNAL/SEPTEMBER 9, 1978/VOL 119 483
Ludiomil® For the Optimum Management of Iron Deficiency
SbII-FE
(ferrous sulfate) hematinic
INDICATIONS: The management of iron deficiency states and anemia. CONTRAINDICATIONS: Iron therapy is contraindicated in the presence of hemochromatosis, hemosiderosis and hemolytic anemia. WARNING: Keep out of reach of children. ADVERSE REACTIONS: Gastro-intestinal side effects such as nausea and gastro-intestinal irritation are rare. Other side effects which have been rarely reported are: vomiting, constipation, diarrhea, abdominal pain and skin rash. PRECAUTIONS: Slow-Fe, like all oral iron preparations, may aggravate existing peptic ulcer, regional enteritis and ulcerative colitis. Iron when given with tetracyclines, binds in equimolecular ratio thus lowering the absorption of tetracyclines. DOSAGE: Prophylaxis: One tablet daily is sufficient to maintain an adequate iron intake during pregnancy and in patients with simple iron deficiency. Iron Deficiency: Depending on the severity, one or two tablets of Slow-Fe daily, usually in one dose. In mild anemias, one tablet daily will usually suffice. For moderate or severe anemias, two tablets daily should be given until hemoglobin levels return to normal.* In severe cases, up to a maximum of 4 tablets daily may be given. In the case of children, one tablet of Slow-Fe daily is a suitable dose for children able to swallow a small tablet. *This physiological process may require a period of up to eight weeks. Once the desired hemoglobin level is attained, the dose can then be reduced to one tablet daily for maintenance to build up the iron reserves over a further 12 to 16 weeks. white, film-coated Slow-Fe tablet contains 160 mg of dried ferrous sulfate (=50 mg elemental iron) in a specially formulated matrix. Packaged in push-through packs containing 30 tablets per sheet and are available in units of 30, 120 and 4,800. References: 1. Product Monograph. Full information available on request.
CIBA DORVAL, OU.BEC. H9S 161
see page 403
cioee
Brief prescribing information, indications Endogenous depressive illness, including the depressed phase of manic-depressive illness (bipolar depression) and involutional melancholia Selected patients suffering severe depressive neurosis. Contraindications Ludiomil (maprotiline) should not be used concomitantly with monoamine oxidase inhibitors; at least fourteen days should elapse between discontinuing one of the interacting drugs and replacing it with the other. Ludiomil is contraindicated in patients with existing severe hepatic or renal damage, a history of severe blood dyscrasias, narrow angle glaucoma, convulsive disorders and during the acute recovery phase following myocardial infarction. Not recommended for use in children. Use in Pregnancy Safe use of Ludiomil during pregnancy and lactation has not been established, therefore, it should not be administered to women of childbearing potential or nursing mothers unless the benefits outweigh the possible hazards. Warnings Extreme caution should be used when Ludiomil (maprotiline) is given to patients with known cardiovascular disease including a history of myocardial infarction, arrhythmias andlor ischemic heart disease. Use with caution in hyperthyroid patients or those on thyroid medication, and in patients with a history of urinary retention, particularly in the presence of prostatic hypertrophy. Close supervision and careful adjustment of dosage is required when administering Ludiomil with anticholinergic or sympathomimetic drugs. Patients requiring concomitant treatment for hypertension should not be given antihypertensives of the adrenergic-neurone inhibitor type, such as guanethidine. Activation of psychosis in schizophrenic patients, hypomanic or manic episodes in patients with cyclic disorders have occurred with tricyclic antidepressants. The use of an antipsychotic drug in these latter two conditions is recommended should they occur in the course of Ludiomil administration. Precautions Seriously depressed patients must be carefully supervised due to the possibility of suicide. Patients should be warned that their responses to alcoholic beverages or other ONS depressants may be exaggerated. Patients should also be cautioned against performing potentially dangerous tasks that require mental alertness and good physical coordination. Periodic blood cell counts and liver function tests are recommended with prolonged therapy. Prior to elective surgery, Ludiomil should be discontinued for as long a period as clinically feasible. Adverse reactions The following adverse reactions have been reported either with Ludiomil or the tricyclic antidepressant drugs: Neurological: numbness, tingling, paresthesias of extremities, incoordination, ataxia, tremors, peripheral neuropathy, extrapyramidal symptoms, seizures, alteration in EEG patterns, tinnitus. Behavioral: confusional states (especially in the elderly) with hallucinations, disorientation, delusions; anxiety, restlessness, agitation, insomnia and nightmares, hypomania, mania, exacerbation of psychosis, decrease in memory, feelings of unreality, weakness and fatigue, drowsiness, dizziness, urinary frequency. Autonomic: dry mouth and, rarely, associated sublingual adenitis; blurred vision, disturbances of accommodation, mydriasis; constipation; paralytic ileus; urinary retention, delayed micturition, dilation of the urinary tract, perspiration, flushing. Cardiovascular: hypotension, hypertension, congestive heart failure, tachycardia, palpitation, myocardial infarction, arrhythmias, heart block, stroke and syncope. Hematologic: bone marrow depression including agranulocytosis, eosinophilia, purpura and thrombocytopenia may occur as an idiosyncratic response. Leukocyte and differential counts should be performed in any patient who develops fever and sore throat during the therapy; the drug should be discontinued if there is evidence of pathological neutrophil depression. Gas trointestinal: nausea or vomiting, anorexia, epigastric distress, diarrhea, bitter taste, stomatitis, abdominal cramps, black tongue, dysphagia, increased salivation, altered liver function. Endocrine: gynecomastia in the male, breast enlargement and galactorrhea in the female, increased or decreased libido, impotence, testicular swelling, elevation or depression of blood sugar levels, weight gain or loss. Allergic or toxic: skin rash, petechiae, urticaria, itching, photosensitization (avoid excessive exposure to sunlight); edema (9eneral or of face and tongue); drug fever, obstructive jaundice, nasal congestion. Dosage Adults Outpatients: initially 25 mg t.i.d., may be increased in increments of 25-50 mg to a maximum of 50 mg q.i.d. Hospital patients: initially 50 mg b.i.d. or tid., may be increased in increments of 25-50 mg to a maximum of 300 mg daily. Elderly patients: generally 25 mg tid. or qid. Maintenance: dosage may be gradually reduced to 75 mg daily or less. A single daily dose of 75 mg to 150 mg at bedtime can be given by virtue of the long half-life of Ludiomil. This would ensure better patient compliance and may obviate the need for hypnotics. Supplied Tablets containing maprotiline hydrochloride, film coated, slightly biconvex: 25 mg, light orange marked CIBA one side and DP on other; 50 mg, orange marked CIBA on one aide and ER on other; 75 mg, coral, scored, marked CIBA on one side and FS on other. Bottles of 50 and 500 tablets. Product Monograph supplied on request. References 1. Trick, K.L.K.: Double-Blind Comparison of Maprotiline (Ludiomil5) with Amitriptyline in the Treatment of Depressive Illness. J. mt. Med. Research, Vol. 3, Suppl. 2, 1975. Edited by J.E. Murphy, Cambridge Medical Publications Ltd., England. pp. 67-70 2. Mathur, G.N.: A Double-Blind Comparative Clinical Trial of Maprotiline (Ludiomil5) and Amitriptyline. J. mt. Med. Research, Vol. 3, Suppl. 2, 1975. Edited by J.E. Murphy, Cambridge Medical Publications Ltd., England. pp. 71-74 3. Singh, A.N., Saxena, B.: Maprotiline (Ludiomil,* CIBA 34,276-BA) and Imipramine in Depressed Outpatients: A Double-Blind Clinical Study. Current Therapeutic Research, Vol. 19, No. 4, April, 1976.4. Product Monograph-Ludiomil5
CIBA DorvaiQue. H95 iBi
.AA .nuts.idi.t hack nnver
C-7117
ilation around the base of the silo. A simple qualitative test for oxides of nitrogen should be developed and be made freely available to farmers so they may know when it is safe to enter their silo. Finally, physicians, especially in rural areas, should be' more aware of this disease and the increased risk of it during the late summer. This study was supported by the Ontario Respiratory Disease Foundation. References 1. NIcHOLs RH: The clinical effects of the inhalation of nitrogen dioxide. Am J Roentgenol 23: 516, 1930 2. LINIx.vIsT T: Nitrous gas poisoning among welders using acetylene flame. Study of 16 cases, including 4 deaths. Acta Med Scand 118: 210, 1944 3. RECKLAKE MR, GOLDMAN HI, RosMAN AR, et al: The long-term effects of exposure to nitrous fumes. Am Rev
Tuberc 76: 398, 1957 4. DARKE CS, WARRACK AJ: Bronchiolitis from nitrous fumes. Thorax 13: 327, 1958 5. HAYHURST ER, Scorr E: Four cases of sudden death in a silo. JAMA 63:
1570, 1914 6. GRAYSON RR: Silage gas poisoning: nitrogen dioxide pneumonia, a new disease in agricultural workers. Ann Intern Med 45: 393, 1956 7. LOWRY T, SCHUMAN LM: "Silo-filler's disease" - a syndrome caused by nitrogen dioxide. JAMA 162: 153, 1956 8. PRYS-ROBERTS C: Principles of treat-
ment of poisoning by higher oxides of nitrogen. Br J Anaesth 39: 432,
1967 9. RAFu 5, GoDWIN MD: Silo-filler's disease. Relapse following latent penod. Arch Pathol Lab Med 72: 424, 1961 10. GAILITIs J, BuRNs LE, NALLY JR:
Silo-fillers disease; report of a case. N Engi J Med 258: 543, 1958 11. MORRISSEY WL, GOULD IA, CARRING-
TON CR, et al: Silo-filler's disease. Respiration 32: 81, 1975 12. COTINELIUs EA, RETLACH EH: Silo-
filler's disease. Radiology 74: 232, 1960 13. RAMIREZ-R J, DOWELL AR: Silofiller's disease: nitrogen dioxideinduced lung injury: long-term follow-up and review of the literature.
Ann Intern Med 74: 569, 1971 14. Scorr EG, HUNT WR . Silo-filler's disease. Chest 63: 701, 1973
15. MosKowlTz RL, LYONS HA, COTrLE HR: Silo-filler's disease. Clinical, phy-
siologic and pathologic study of a patient. Am J Med 36: 457, 1964 16. SCHELL HW: Chronic silo-filler's disease. Conn Med 22: 546, 1958 17. LEIB GM, DAVIs WN, RROWN T, et
al: Chronic pulmonary insufficiency secondary to silo-filler's disease. Am I Med 24: 471, 1958
