POISONI G MANAGEM E T

Drug Safety 6 (5): 332·338, 1991 0114-5916/91/0009·0332/$03.50/0 © Adis International Lim ited. All rights reserved. DRS1035

Hyperbaric Oxygen Treatment for Carbon Tetrachloride Poisoning Keith K. Burkhart, Alan H. Hall, Rocco Gerace and Barry H. Rumack Rocky Mountain Poison and Drug Center, University of Colorado Health Sciences Center, Denver General Hospital, Denver, Colorado, USA, and Department of Medicine, Division of Emergency Medicine, University of Western Ontario, Victoria Hospital, London, Ontario, Canada

Contents 332 333 333 333 333 333 335 336 336

Summary

Summary I. Availability of Carbon Tetrachloride 2. Pathophysiology 3. Clinical Presentation 4. Hyperbaric Oxygen Therapy Studies 4.1 In Vitro Studies 4.2 In Vivo Studies 5. Case Reports From the Literature 6. Conclusions

Carbon tetrachloride (CCI4) undergoes hepatic reductive metabolism to trichloromethyl (0 CCl3) and peroxytrichloromethyl (CC1300 0) free radicals, toxic intermediates which may initiate hepatocellular damage. Recent investigations have demonstrated a potential role for hyperoxia and hyperbaric oxygen as therapeutic interventions for CCl4 poisoning. Elevated oxygen concentrations in vitro and in vivo reduce lipid peroxidation and hepatotoxicity. In vivo studies of hyperbaric oxygen following administration of CCI4 in a rat model have shown improved survival and decreased hepatotoxicity. Case reports of human poisoning, with potentially lethal ingested doses of CCl4, also suggest a potential role for treatment with hyperbaric oxygen. Hyperoxia may act by altering the metabolism of CCI4. These studies and case reports support the recommendation that 100% normobaric and hyperbaric oxygen should be treatment considerations for CCI4 poisoning.

Carbon tetrachloride (CCI4) is a potent hepatotoxin, reported to cause death with ingestion of as little as Sml (Stewart et al. 1963). The hepatotoxicity appears to result from its metabolism to free

radicals (Gordis 1969). Hyperbaric oxygen has been suggested as a therapy for CCl4 poisoning (U ndersea and Hyperbaric Medical Society 1986). CCl4 overexposure occurs infrequently, precluding large

Hyperbaric Oxygen for CCl4 Poisoning

clinical trials with and without hyperoxia treatment. Available experimental evidence and case reports of CCl4 poisoning treated with hyperbaric oxygen must therefore be evaluated to determine the potential benefit of this therapeutic intervention.

1. Availability of Carbon Tetrachloride CCl4 is used in the manufacture of fluorocarbon refrigerants, aerosol propellants, and semiconductors (ACGIH 1986; Sax & Lewis 1987; Sittig 1985). It is used as a metal degreaser, an insecticidal grain fumigant, and also serves as a solvent for fats, oils, lacquers, varnishes, rubber, waxes and resins (Proctor et al. 1988; Sax & Lewis 1987; Sitti 1985). Previously, CC14 was used as a drycleaning agent and in fire extinguishers, but its toxicity led to replacement by trichloroethylene, methylchloroform and other halogenated hydrocarbons (Kelley et al. 1975). The US FDA has banned the use of CCI4 in all products, except where it is an unavoidable by-product (EUenhorn and Barceloux 1988). Access to this compound in the United States (and in many other countries) is therefore limited.

2. Pathophysiology CCl4 is a colourless, nonflammable liquid with a sweet, ether-like odour (ACGIH 1986; Sax & Lewis 1987, 1989). It is absorbed by inhalation, ingestion and through intact skin. Most of an absorbed dose is excreted unchanged by the lungs; the remainder is metabolised by the liver. Hepatic NADPH-dependent cytochrome P450 reductase cleaves one of the carbon-chlorine bonds to form the trichloromethyl (0 CC13) free radical, which may be responsible for initiating a free radical cascade resulting in hepatocellular necrosis (fig. I) [Burk et al. 1984; Kubic & Anders 1980; Mico & Pohl 1983; Poyer et al. 1978]. Histologically, hepatic injury is a pattern of centrilobular necrosis similar to that seen in paracetamol (acetaminophen) poisoning. Acute renal tubular necrosis has also been reported (Luse & Wood 1967; Perez et al. 1987).

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3. Clinical Presentation There is wide individual variability in the occurrence of toxic effects after CCl4 exposure. Sudden deaths secondary to cardiac arrhythmias or respiratory depression have been reported (Ruprah et al. 1985). Some patients with minimal initial symptomatology have presented days after exposure with hepatic and, in some cases, renal failure (Fogel et al. 1983). Most patients first develop nausea, vomiting, diarrhoea and abdominal pain (New et al. 1962). A typical clinical feature in CCI4 poisoning is CNS depression with dizziness, confusion, or coma (Luse & Wood 1967; Ruprah et al. 1985).

4. Hyperbaric Oxygen Therapy Studies 4.1 In Vitro Studies

Early in vitro experiments studied the effect of oxygen tension on CCl4 toxicity. Stacey et al. (1982) incubated rat hepatocyte suspensions in flasks containing CCl4 under carbogen (95% 02 and 5% C02) or air at I atmosphere (I ATA). Under room air (approximately 21 % 02), levels of some markers of lipid peroxidation, ethane and thiobarbituric acid reactants, were increased. The increased oxygen concentration of carbogen (95% 02) prevented an increase in lipid peroxidation. Leakage of lactate dehydrogenase, indicating cell death, also occurred under an air, but not carbogen, atmosphere. In another study, the steady-state partial pressure of oxygen was varied from I to 80mm Hg in rat liver microsomes incubated with CCl4 (Noll & De Groot 1984). Under hypoxic conditions (1 to IOmm Hg), there was a 5-fold increase in oxygen uptake, suggesting increased peroxyl radical formation and activity, compared to a 2-fold increase in these parameters under 80mm Hg 02. Malondialdehyde formation, another marker of lipid peroxidation, increased 20-fold under hypoxic conditions compared to only 4-fold at an oxygen partial pressure of80mm Hg. The mechanism of the hepatoprotection afforded by oxygen has not been determined; however, elevated hepatic oxygen tensions may poten-

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NADPH Reductase

.c~\

CCI4-----+

Covalent binding

Covalent binding (14C to lipid and protein)

CI-C-CI CHCI3 (Chloroform)

II

o (Phosgene)

C2CI6 (Hexachloroethane)

ro'

dienes

PUFA-PUFA (cross-linking)

1

Lipid peroxidation

M_L 1~M ,

Thiobarblturlc acid reactive substances

Fig. 1. Proposed metabolic pathway of carbon tetrachloride. PUFA = polyunsaturated fatty acid. In theory, oxygen may inhibit NADPH reductase and therefore the hepatic metabolism and toxicity of CCI4. High 02 tensions probably shift the conversion of· CCI3 towards the CC1300· pathway. It is proposed that the highly reactive CQ300·, compared with· CCl), may destroy the enzyme system preventing production of further toxic free radical intermediates [adapted from Burk et al. (1984), Kubic & Anders (1980), Mico & Pohl (1983), Packer et al. (1978) and Comporti (1985»).

tially alter the metabolism of CCI4. Oxygen may inhibit the NADPH-dependent reducing enzyme system, resulting in formation of less • CCI3 free radical. Elevated oxygen tensions may also promote formation of C0300 • when • C03 is formed (Kubic & Anders 1980; Poyer et al. 1978). This highly reactive CC1300· species may destroy the enzyme system, thereby preventing further production of the toxic intermediates, • CCl) or CCl)OO·, while the less reactive • CCl) may diffuse away to produce more distant free radical damage leaving the enzyme system intact to produce further toxic metabolites. An in vitro study (Burk et al. 1986) supports this proposed mechanism: chloroform production from CCl4 metab-

olism fell dramatically as the percentage of oxygen was increased from 0 to 5%; chloroform was not detected in 21 % 02. Thiobarbituric acid-reactive substances were not produced in the absence of oxygen, as lipid peroxidation cannot occur without some oxygen being present. Oxygen I% produced the largest amount of lipid peroxidation, which then decreased dramatically with increasing oxygen tension (Burk et al. 1986). Glutathione protects hepatocytes from lipid peroxidation during oxidative stress, and it may be more effective at higher oxygen tensions; the presence of glutathione in hepatocyte cultures under air or hyperbaric atmospheres did not alter chloroform production from CCl4 metabolism, but sig-

Hyperbaric Oxygen for CC14 Poisoning

nificantly reduced lipid peroxidation (Burk et al. 1984). Peroxidation was further reduced when glutathione was present in the cultures at higher oxygen tensions. Covalent binding of 14C from radiolabelled CC14 occurred at 0% oxygen. In the absence of oxygen, this binding would represent only • CC13 formation and free radical activity (fig. 1). Increasing the percentage of 02 reduced this covalent binding of 14C to rat microsomes. Glutathione had little effect at 0 and 1% 02, but produced significant reductions in binding at concentrations of 3, 5, and 21% 02. The above data also support previous findings of hepatoprotection in CCl4-poisoned rats and humans treated with Nacetylcysteine, believed to be a glutathione precursor (DeFerreyra et al. 1974; Laurenzi et al. 1986; Mathieson et al. 1985).

4.2 In Vivo Studies Two early studies of experimental CC14 poisoning in rats treated with hyperbaric oxygen demonstrated increased survival rates (Montani & Perret 1967; Rapin et al. 1967). In both studies rats were given CCI4, 250 ~l/100g by gavage, followed by hyperbaric oxygen. In 1 study, the control group had an 80.4% mortality rate, while a single 6 hour session of hyperbaric oxygen at 2 ATA lowered the mortality rate to 8.8% (Rapin et al. 1967). When hyperbaric oxygen was delayed for 24 hours, however, the mortality rate was only decreased from 80.4% to 47%. As human hyperbaric oxygen protocols usually involve periodic treatments, these authors tested a regimen of 6 treatments at 2 ATA given for 2 hours each, separated by 4 hours of breathing room air; this regimen resulted in a mortality rate of 36.8%. Histologically, at 24 hours the hyperbaric oxygen-treated rats had periportal sparing and, by 48 hours, marked regeneration of the liver compared to controls. Montani & Perret 1967 used fasted rats in their study: this technique is frequently used in animal models to augment the hepatotoxicity of free radical-generating toxic agents; glutathione depletion is a proposed mechanism. Treatment with ambient air versus hyperbaric oxygen at 1.6 ATA in fed ver-

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sus fasted CCl4-poisoned rats were compared. The combined 6-day survival of hyperbaric oxygenversus ambient air-treated rats was increased significantly from 20 to 66%. Fasting may have contributed to the higher mortality rate in this study. In mice, however, there were no statistically significant differences in liver or renal parameters when intraperitoneal injections of 10 ~l of CC4 were followed by hyperbaric oxygen (Merola et al. 1967). Later experiments investigated C04 toxicity with varying oxygen concentrations. In 1 of these, rats inhaled CC14 in the presence of 6, 12,21, and 100% oxygen (Shen et al. 1982). 12% 02 produced the greatest increase in alanine amino transferase (ALT) activity. There was a statistically significant increase in 14C covalent binding to lipids and protein from radi01abelled CC14, as well as increased conjugated diene formation (evidence of lipid peroxidation) in the 12% vs the 21% 02 group. Covalent binding and conjugated diene formation indicate increased generation of free radicals. The 12% 02 group also had more extensive centrilobular necrosis than the 21 % 02 group. These results suggest that hypoxia enhances the toxicity of CC4. Marzella et al. (1986) compared the effect of various oxygen concentrations during hyperbaric oxygen treatment after CC14 poisoning. Oxygen at 3 ATA in a chamber containing 20% or 60% oxygen was not hepatoprotective when rats were administered intraperitoneal CC14. When 100% oxygen at. 2.8 ATA was begun immediately after injection of the toxin, 30 minutes of treatment significantly reduced the elevations of liver function tests. These results suggest that increased oxygen tension is responsible for hepatoprotection, and not simply hyperbaric pressure. A lesser degree of protection occurred when rats were pretreated for 5 days with phenobarbital, an inducer of cytochrome P450 enzymes. A decreased protective effect was also noted when there was a delay of 1 hour before beginning hyperbaric oxygen treatment. When hyperbaric oxygen was begun 6 hours after CC14 injection, rats had elevated liver function tests compared with the control group. These results suggest that after a

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critical amount of free radical activity has begun, oxygen may become a substrate and promote further free radical toxicity. Survival, not serum transaminase elevations, however, may be a better outcome measure of the effectiveness of a therapeutic intervention in preventing hepatic failure in CCl4 poisoning. Although very large elevations of serum transaminases may occur, if enough of the liver is spared, it may regenerate. Another study evaluated survival when rats were treated with 6 hours of hyperbaric oxygen at 2 ATA following oral administration of 250 ~l/lOOg of CCI4; compared to inhalation of ambient air, survival increased from 31 to 96% and ALT elevations were decreased (Burk et al. 1984). However, 100% normobaric oxygen also increased survival to 79%. A delay of 12 to 24h before beginning hyperbaric treatment increased survival to 50%, but the statistical significance of this result was not reported. Additional studies have evaluated the effect of delayed versus immediate treatment with hyperbaric oxygen. In I rat study the start of hyperbaric oxygen treatment was delayed for Ih (Bernacchi et al. 1984). While there was no change in mortality between the immediate and delayed treatment groups, only the delayed hyperbaric oxygen group developed elevations of hepatic transaminases, histological evidence of hepatic necrosis and the presence of conjugated dienes, markers of lipid peroxidation. In another rat study a I-hour vs a 4-hour delay to hyperbaric oxygen was studied (Troop et al. 1986). There was a statistically significant decrease in survival, 76 vs 41%, in the 4-hour delay group. The possible hepatoprotective mechanism of hyperbaric oxygen has been investigated (Burk et al 1984). Following CCl4 poisoning, hyperbaric oxygen did not lower either blood or hepatic CCl4 concentrations, implying that absorption from the gastrointestinal tract, hepatic blood flow and hepatic uptake were not altered. Treatment with hyperbaric oxygen, compared to air at 2 AT A for 3h, inhibited production of chloroform and ethane in rats. Decreased chloroform production suggests that hyperbaric oxygen may inhibit the metabolism of

CCI4. Hyperbaric oxygen therapy may promote the formation of CC1300. from • CCl3 when it is formed, resulting in potentially hepatoprotective effects, discussed in the in vitro studies section above (Burk et al. 1986; Kubic & Anders 1980; Poyer et al. 1978).

5. Case Reports From the Literature A comatose 28-year-old man was mistakenly treated for carbon monoxide poisoning with hyperbaric oxygen at 2.5 ATA for 45 minutes (Truss & Killenberg 1982). On awakening, this patient admitted ingestion of CCl4 250ml approximately 4 hours before treatment. An abdominal radiograph showed the presence of a radiopaque substance (CCI4) in the gastrointestinal tract. The patient was treated with hyperbaric oxygen at 2 ATA for 2 hours twice daily for 7 days, followed by 4 days with I similar treatment/day. ALT did not rise above 800 U/L. Antioxidants, vitamins E and C were also given, however. A 39-year-old woman ingested CCl4 150ml (Larcan et al. 1973). Hyperbaric oxygen at 3 AT A was administered for 1.5 hours 3 times/daily, beginning within 24 hours of ingestion, and continued for 23 sessions. This patient developed a peak aspartate amino transferase (AST) of 3000 U /L, but survived. A 30-year-old man recovered after ingesting 30ml of CCl4 (Zearbaugh et al. 1988). He received 13 hyperbaric oxygen treatments in addition to gastric lavage and haemodialysis. Lamy et al. (1970) reported anecdotal success of hyperbaric oxygen in treating other hepatotoxins. Death has resulted from ingestion of as little as 5ml, while ingestions greater than 100mi are usually considered potentially lethal (Stewart et al. 1963). Therefore, hyperbaric oxygen may have contributed to the favourable outcomes in these cases.

6. Conclusions Currently available experimental studies and anecdotal case reports of successful use of hyperbaric oxygen therapy in CCl4 poisoning demon-

Hyperbaric Oxygen for CC14 Poisoning

strate the potential therapeutic benefit of this treatment, although the mechanism has not clearly been established. Diminished CCl4 hepatotoxicity is evidenced by decreased elevations ofliver function studies, a histological picture of less severe centrilobular hepatic necrosis, and diminished production of markers of free radical damage. Survival studies have demonstrated decreased mortality in the rat model. The hepatoprotection afforded by hyperbaric oxygen, however, seems to diminish when treatment is delayed. Further studies are needed to define the period after acute poisoning when there may be benefit from this therapy. As 100% normobaric oxygen also demonstrated some therapeutic efficacy, it appears reasonable to consider either form of hyperoxia for patients exposed to potentially significant amounts of CCI4. NAcetyJcysteine treatment has also shown some potential benefit in CCl4 poisoning, and should be studied in conjunction with hyperoxia therapy.

Acknowledgement Dr Burkhart's fellowship was supported in part by Smith, Kline, and French Laboratories.

References ACGIH. Documentation of the threshold limit values and biological exposure indicies, 5th ed. American Conference of Government Industrial Hygiene, pp. 109-110, Cincinnati, 1986 Bernacchi A, Myers R, Trump BF, Marzella L. Protection of hepatocytes with hyperoxia against carbon tetrachloride-induced injury. Toxicologic Pathology 12: 315-323, 1984 Burk RF, Lane JM, Patel K. Relationship of oxygen and glutathione in protection against carbon tetrachloride-induced hepatic microsomal lipid peroxidation in covalent binding in the rat: rationale for the use of hyperbaric oxygen to treat carbon tetrachloride ingestion. Journal of Clinical Investigation 74: 1996-2001, 1984 Burk RF, Reiter R, Lane 1M. Hyperbaric oxygen protection against carbon tetrachloride hepatotoxicity in the rat: association with altered metabolism. Gastroenterology 90: 812-818, 1986 Comporti M: Biology of disease: lipid peroxidation and cellular damage in toxic liver injury. Laboratory Investigation 53: 599622, 1985 DeFerreyra EC, Castro JA, Diaz Gomez MI, et al. Prevention and treatment of carbon tetrachloride hepatotoxicity by cysteine: studies about its mechanism. Toxicology and Applied Pharmacology 27: 558-568, 1974 Ellenhorn MJ, Barceloux 00. Hydrocarbon products: carbon tetrachloride. Medical Toxicology, pp. 969-972, Elsevier, New York, 1988 Fogel RP, Davidmand M, Poleski MH, et al. Carbon tetrachloride poisoning treated with hemodialysis and total parenteral

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nutrition. Canadian Medical Association Journal 128: 560-561, 1983 Gordis E. Lipid metabolites of carbon tetrachloride. Journal of Clinical Investigation 48: 203-209, 1969 Kelley WD, Ligo RN, Mitchell FL, et aI. Criteria for a recommended standard: occupational exposure to carbon tetrachloride. US Department of Health, Education and Welfare, HEW Publication No. (NIOSH) 76-133, 1975 Kubic VL, Anders MW. Metabolism of carbon tetrachloride to phosgene. Life Sciences 26: 2151-2155, 1980 Lamy ML, Hanquet MM. In Wada & Iwa (Eds) Proceedings of the 4th International Congress in Hyperbaric Medicine, pp. 517-522, Williams and Wilkins, Baltimore, 1970 Larcan A, Laprevote-Heully MC, Lambert H, et al. Intoxication par ingestion d'une dos massive de tetrachlorure de carbone: guerison en relation probable avec une oxygenotherapie hyperbare precoce. Journal Europeen de Toxicologie 6: 286-289, 1973 Laurenzi RG, Locatelli C, Brucato A, Maccarine D. N-Acetylcysteine: a proposal for therapy in acute poisoning due to highly hepatotoxic organic solvents. Abstract III World Congress of the World Federation of Associations of Clinical Toxicology and Poison Control Centers. XII International Congress of the European Association of Poison Control Centres, 27-30 August, 1986 Luse SA, Wood WG. The brain in fatal carbon tetrachloride poisoning. Archives of Neurology 17: 304-312, 1967 Marzella L, Muhvich K, Myers RAM. Effect ofhyperoxia on liver necrosis induced by hepatotoxins. Virchows Archiv B - Cell Pathology Including Molecular Pathology 51: 497-507, 1986 Mathieson PW, Williams G, MacSweeney JE. Survival after massive ingestion of carbon tetrachloride treated by intravenous infusion of acetylcysteine. Human Toxicology 4: 627-631, 1985 Merola L, Bimonte D, Cacciatore L, et al. Observazioni sulla influenza della ossigenazione iperbarica sulla intossicazione acuta del topo da CCL4. Bolletino Della Societa Italiano Di Biologia Sperimentale 43: 1760-1762, 1967 Mico BA, Pohl LR. Reductive oxygenation of carbon tetrachloride: trichloromethylperoxyl radical as a possible intermediate in the conversion of carbon tetrachloride to electrophilic chlorine. Archives of Biochemistry and Biophysics 225: 596-609, 1983 Montani S, Perret C. Oxygenation hyperbare dans I'intoxication experimentale au tetrachlorure de carbon. Revue Francaise Etudes Cliniques et Biologiques 12: 274-278, 1967 New PS, Lubash GD, Scherr L, et al. Acute renal failure associated with carbon tetrachloride intoxication. Journal of the American Medical Association 181: 903-906, 1962 Noll T, De Groot H. The critical steady-state hypoxic conditions in carbon tetrachloride-induced lipid peroxidation in rat liver microsomes. Biochimica et Biophysica Acta 795: 356-362, 1984 Packer JE, Slater TF, Willson RL. Reactions of the carbon tetrachloride-related peroxy free radical (CCI302) with amino acids: pulse radiolysis evidence. Life Sciences 23: 2617-2620, 1978 Perez AJ, Courel M, Zobrado J, et al. Acute renal failure after topical application of carbon tetrachloride. Lancet I: 515-516, 1987 Poyer JL, floyd RA, McCay PB, et al. Spin-trapping of the trichloromethyl radical produced during enzymic nadph oxidation in the presence of carbone tetrachloride or bromotrichloromethane. Biochimica et Biophysica Acta 539: 402-409, 1978 Proctor NH, Hughes JP, Fischman ML. Chemical hazards of the workplace, 2nd ed.,pp. 153-154, IB Lippincott Co, Philadelphia, 1988 Rapin M, Got C, Le Gall JR, et al. Effet de I'oxygene hyperbare sur la toxicite tetrachlorure de carbone chez Ie rat. Revue Francaise Etudes Oinique et Biologique 12: 594-599, 1967 Ruprah N, Mant TGK, flanagan RJ. Acute carbon tetrachloride

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poisoning in nineteen patients: implications for diagnosis and treatment. Lancet I: 1027-1029, 1985 Sax NI, Lewis RJ. Hawley's condensed chemical dictionary, 11th ed., p. 222, Van Nostrand Reinhold Company, New York, 1987 Sax NI, Lewis RJ. Dangerous properties of industrial materials, 7th ed., pp. 714-716, Van Nostrand Reinhold Company, New York, 1989 Shen ES, Garry ES, Anders MW. Effect of hypoxia on carbon tetrachloride hepatotoxicity. Biochemical Pharmacology 31: 3787-3793, 1982 Sittig M. Handbook of toxic and hazardous chemicals and carcinogens, 2nd ed., pp. 194-196, Noyes Publications, Park Ridge, 1985 Stacey NH, Ottenwalder H, Kappus H. CCl4-induced lipid peroxidation in isolated rat hepatocytes with different oxygen concentrations. Toxicology and Applied Pharmacology 62: 421427, 1982 Stewart RO, Boettner EA, Southworth RR, et al. Acute carbon tetrachloride intoxication. Journal of the American Medical Association 183: 994-997, 1963

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Troop BR, Majerus T, Bernacchi A, Belzerb H, Myers RAM. Hyperbaric oxygenation improves survival in rats poisoning with carbon tetrachloride. Journal of Hyperbaric Medicine I: 157161,1986 Truss CO, Killenberg PO. Treatment of carbon tetrachloride poisioning with hyperbaric oxygen. Gastroenterology 82: 767-769, 1982 Undersea and Hyperbaric Medical Society, Inc. Hyperbaric oxygen therapy: a committee report. UMS Publication 30 CR(HBO) 1986 Zearbaugh C, Gorman OF, Gilligan JE. Carbon tetrachloride/ chloroform poisoning: case studies of hyperbaric oxygen in- the treatment of lethal dose ingestion. Undersea Biomedical Research 15 (Suppl.): 44, 1988

Correspondence and reprints: Dr K.K. Burkhart, The Milton S. Hershey Medical Center, The Pennsylvania State University, Hershey, PA 17033, USA.

Errata Vol. 6, No.1, 1991: The final sentence of section 1.1 on page 11 should read: Four cases of allergic vasculitis were spontaneously reported from postmarketing surveillance involving 1.5 million patients; 3 appeared to be unrelated to otloxacin. Vol. 6, No.4, 1991: The second sentence of the heading to table I on page 268 should read: All patients were reported to have recovered except No.8 (unknown) and No. 22 (died)

Hyperbaric oxygen treatment for carbon tetrachloride poisoning.

Carbon tetrachloride (CCl4) undergoes hepatic reductive metabolism to trichloromethyl (.CCl3) and peroxytrichloromethyl (CCl3OO.) free radicals, toxic...
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