Background: Nickel carbonyl is formed when carbon monoxide comes into contact with active nickel. The inhaled nickel carbonyl is rapidly absorbed and distributed mainly to the lungs, brain, adrenal glands, and kidneys. In severe cases, acute nickel carbonyl exposure has been reported to cause death.
Design: Descriptive study.
Patients: Seven young men presented with fever, chills, substernal pleuritic chest pain, and exertional dyspnea. Extensive microbiological and toxicological investigations (including blood, urine, and bronchial specimens) for known pathogens and occupational toxins were performed. The clinical course and radiologic findings of each patient, including autopsy findings of three patients who died, were described.
Results: Four patients received treatment in the ICU. Elevated urinary nickel concentration was detected in all patients. Results of extensive microbiological investigations were unremarkable. No patients received chelating agents. Pulmonary consolidation, edema, hemorrhage, and fibrosis were observed at autopsy in patients who died. An out-of-date chemical used during neutralization of nickel waste was implicated as the source of nickel carbonyl poisoning.
Conclusions: High mortality was reported in patients who presented subacutely following nickel carbonyl exposure. Further studies should be performed to clarify the role of chelation therapy in the subacute phases following nickel carbonyl exposure.
Key words: chelation therapy; clinical features; nickel carbonyl
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Nickel carbonyl or nickel tetracarbonyl, Ni[(CO).sub.4], is a toxic, colorless, highly volatile, and flammable liquid that is formed when carbon monoxide comes into contact with active nickel. Nickel carbonyl is used in the extraction of nickel (Mond process), gas plating, and as a catalyst and reactant in chemical synthesis, and is usually encountered as a vapor that is rapidly absorbed after inhalation. Acute exposure to nickel carbonyl has been reported to result in inhalational pneumonitis that has been associated with fatal outcome. (1-5) We report the clinical course, radiologic, and autopsy findings following nickel carbonyl poisoning at a waste treatment factory in Singapore.
MATERIALS AND METHODS
Characterizing the Clinical Illness
Seven patients who worked at a waste-processing factory presented within 12 h of each other with high fever, chills, substernal pleuritic chest pain, and exertional dyspnea of 3 days in duration. The patients had marked leukocytosis and diffuse chest radiographic infiltrates. They were admitted through the emergency departments of Alexandra Hospital and National University Hospital, Singapore, and extensive investigations were performed after a cluster outbreak of acute respiratory illness was identified. The waste-processing factory where they worked was involved in the collection of hazardous waste chemicals, neutralization of acid waste, recycling of solvent waste, and incineration of waste oil sludge. Three days before the hospital admission, the patients had worked for 4 h (from 2 to 6 PM) in close proximity to a plant where neutralization of nickel was in progress. They did not have any direct contact with the nickel waste and had worn dust facemasks.
Microbiological Investigations
Initial microbiological investigations included the following: respiratory secretions (sputum and tracheal aspirate specimens) that were analyzed for conventional bacteria (with blood, chocolate, and MacConkey agars), Legionella pneumophila (with buffered charcoal yeast extract agar medium), and Mycobacteria (with Lowenstein-Jensen medium). Gram staining and auramine-rhodamine-stained smears were examined to search for bacterial or acid-fast morphotypes. Single or paired (when available) serum samples were tested for Mycoplasma pneumoniae and Chlamydia pneumonia and Chlamydophila psittaci (microimmunofluorescence kit; MRL Diagnostics; Cypress, CA). Urinary antigen detection was performed for Legionella pneumophila and pneumococcus.
Occupational Investigations
Occupational toxins tested included estimation of the concentration of heavy metals (lead, cadmium, nickel), sulfide, and solvent (n-hexane, methyl chloroform, ethyl acetate, methyl ethyl ketone, methyl butyl ketone, benzene, trichloroethylene, chloroform, perchloroethylene, toluene, isobutanol and xylenes) in blood and urinary specimens. Samples of concrete chips from the chemical plant were sent for scanning electron microscopic examination, and air samples were collected and analyzed for heavy metals. The heavy metals were analyzed using graphite furnace atomic absorption spectrophotometry; sulfide, using Conway microdiffusion cell and an ion-specific electrode ([S.sup.2-] and C[N.sup.-]); and the solvents, using head-space gas chromatography.
RESULTS
Characterizing the Clinical Illness
The clinical symptoms and signs, laboratory and radiologic findings, and treatment outcomes were smnmarized in Table 1. Patients A, B, and C were intubated and required ventilatory support. High-resolution CT of thorax was performed on patient E (Fig 1). The clinical course of hospitalization of patients A, B, and C who died was summarized in Table 2, while autopsy findings of these patients were summarized in Table 3. Results of repeated microbiological investigations, including BAL specimens performed in two patients who required mechanical ventilation, were negative. Patients who survived were asymptomatic on outpatient review 6 months later.
[FIGURE 1 OMITTED]
Microbiological and Occupational Investigations
Microbiological investigations were unremarkable, and occupational investigations revealed elevated levels of urinary nickel concentration in all patients. Urinary nickel concentrations ranged from 19.8 to 78.5 [micro]g/L on days 8 to 15 following exposure (normal, 2 to 10 [micro]g/L). (6) The onset of initial symptoms of these patients coincided with the neutralization process, which involved the use of high concentration of 3.6% nickel (usual concentration of nickel, 0.1%) and a complexing agent. Occupational investigations of the neutralization processes and further simulation studies suggested the use of an out-of-date complexing agent (Metalplex; Techform, Technical University of Munich; Munich, Germany) as the likely cause of nickel carbonyl release. According to the manufacturer of Metalplex, the product is thermosensitive (at < 30[degrees]C) and is chemically stable for 6 months. Crystallization occurs when these conditions are violated, resulting in the formation of tetramethylthiuram disulfide and other decomposition products like sulfur, carbon monoxide, and carbon dioxide. We postulate that the carbon monoxide produced could react with the nickel in the waste in the presence of sulfide in alkaline medium to form toxic amounts of nickel carbonyl fumes.
DISCUSSION
We report the clinical, laboratory, radiologic, and postmortem findings of a cluster of patients who presented subacutely following an industrial accident at a waste treatment factory. The subacute presentation, 3 days following exposure, precluded the use of chelation agents such as diethyldithiocarbamate and disulfiram. A high mortality was reported in three of the seven patients in whom pneumothorax preceded death. A timeline chart for the seven patients was shown in Figure 2. Autopsy findings in these patients revealed generalized interstitial lung fibrosis. Further investigations identified the use of an out-of-date heavy metal-complexing chemical during neutralization of nickel waste as the likely source of nickel carbonyl fumes.
[FIGURE 2 OMITTED]
Symptoms of nickel carbonyl poisoning may develop insidiously hours or even days after inhalation of nickel carbonyl vapors. Initial symptoms are usually mild and not specific. These include frontal headache, dizziness, and occasionally nausea and vomiting. Delayed symptoms, such as chest pain, hemoptysis, and cyanosis, have been reported to occur > 12 to 24 h after exposure. (3) In many cases of accidental poisoning, nickel carbonyl was not recognized as the offending agent until several days after exposure. (2) The primary injury occurs in the pulmonary alveoli, with maximum severity occurring from the fourth to the sixth days after exposure. In cases with fatal outcomes, the main pathologic changes occur in the lungs, liver, and brain and, less commonly, the kidney, liver, and adrenal glands. Changes within the lung include capillary congestion, interstitial edema, interstitial cellular proliferation, fibrinous intra-alveolar exudates, and hypertrophy of the alveolar lining cells (Fig 3). (7)
[FIGURE 3 OMITTED]
Nickel compounds are unique because in vapor form it is highly absorbed compared to other metal compounds in vapor form. In contrast to a rapid absorption and excretion of nickel compounds in the urine, nickel compounds accumulate within the connective tissues of the lung, which delay its clearance. (8) The slower distribution of nickel compounds may explain the adverse outcomes observed in patients who presented subacutely following nickel carbonyl exposure and the development of lung fibrosis found at autopsy and pneumothorax prior to clinical deterioration.
Chelation agents such as diethyldithiocarbamate and disulfiram are investigational drugs used to treat nickel carbonyl poisoning. Even though encouraging results have been reported in animal studies, (9-11) information on its use in humans has been limited to case reports and case series. (2,4,12) The infrequent incidence and delayed recognition of nickel carbonyl poisoning pose methodologic constraints to the conduct of a clinical study to evaluate the role of chelation therapy in nickel carbonyl poisoning. Our experience suggests that chelation therapy is not a requisite for recovery, as four of our patients made complete recoveries despite severe respiratory failure developing. Further studies should be performed to clarify the role of chelation therapy in nickel carbonyl poisoning, especially among those who present within the delayed phases of exposure.
ACKNOWLEDGMENT: We thank the nursing and medical staff of the ICUs of Alexandra Hospital and National University Hospital; Dr. Kenneth Choy and Ms. Oei Hun Ping from the Occupational Health Department, Ministry of Manpower Singapore; Drs. Woo Soo On and Patrick Chow Yue Thong of the Health Sciences Authority; and staff of the Defense Science Organization, who treated and assisted in the investigation.
REFERENCES
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(8) Barceloux DG. Nickel. J Toxicol Clin Toxicol 1999; 37:239-358
(9) Baselt RC, Sunderman FW, Mitchell J, et al. Comparisons of antidotal efficacy of sodium diethyldithiocarbamate, D-penicillamine and triethyletetramine upon acute toxicity of nickel carbonyl in rats. Res Commun Chem Pathol Pharmacol 1977; 18:677-688
(10) Sunderman FW Sr. Efficacy of sodium diethydithiocarbamate (Dithiocarb) in acute nickel carbonyl poisoning. Ann Clin Lab Sci 1979; 9:1-10
(11) Baselt RC, Hanson VW. Efficacy of orally-administered chelating agents for nickel carbonyl toxicity in rats. Res Commun Chemical Pathol Pharmacol 1982; 38:113-124
(12) Sunderman FW, Sunderman FW Jr. Nickel poisoning, VIII: Dithiocarb; a new therapeutic agent for persons exposed to nickel carbonyl. Am J Med Sci 1958; 236:26-31
* From the Department of Medicine (Drs. Seet and Lee), National University Hospital; Department of Medicine (Dr. Johan), Alexandra Hospital; Centre for Forensic Medicine (Dr. Teo), Health Sciences Authority; and Occupational Health Department (Dr. Gan), Ministry of Manpower, Singapore.
Correspondence to: Raymond CS. Seer, MRCP, Department of Medicine, National University Hospital, 5 Lower Kent Ridge Rd, Singapore 119074; e-mail: raymond_seet@nus.edu.sg
COPYRIGHT 2005 American College of Chest Physicians
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