Cardiopulmonary Effects of Acute Thallium Poisoning

Cardiopulmonary Effects of Acute Thallium Poisoning* DavidS. Roby, M.D.;t Alan M. Fein, M.D., F.C.C.P.;t Richard H. Bennett, M.D.;§ Laura S. Morgan, M.D.;II Jacob Zatuchni, M.D.; ~ and Michael L. Lippmann, M.D., F. C. C .P. #

Gastrointestinal distress and alopecia are the most commonly reported symptoms of acute thallium intoxication; however, cardiac and pulmonary disease may dominate the

Thallium intoxication was an important problem in the first half of the century when thallium was used as a rodenticide, insecticide, and topical depilatory. Today, it continues to be used industrially in the production of optic lenses, low-temperature thermometers, semiconductors, pigments, and scintillation counters. Reduced availability has led to the reporting of very few cases of true poisoning; however, sporadic cases do occur, usually secondary to accidental or suicidal ingestion. Most descriptions in textbooks 1 stress the acute gastrointestinal manifestations of thallium intoxication, especially pain, diarrhea, and hemorrhage, which are fOllowed rapidly by central nervous system dysfunction, including ataxia and coma. Alopecia is considered the hallmark of chronic thallium intoxication. Descriptions of myocardial disease are usually limited to electrocardiographic abnormalities and sinus tachycardia. Pulmonary disease is rarely referred to as a complication of thallium intoxication and is cited only as a cause of respiratory failure .31 We report four cases that indicate that, contrary to previously reported descriptions of acute thallium intoxication, cardiac and pulmonary disease may dominate the acute stages of this illness. *From the Departments of Medicine (Pulmonary and Critical Care Divisions) and Neurology, Albert Einstein Medical Center Northem Division, and Episcopal Hospital, Philadelphia. tNeurology Department, Jeanes Hospital, Philadelphia. iPresently Associate Professor, . State University of New York Stony Brook Medical School and Chief, Pulmonary-Critical Care, Nassau Hospital, Mineola, New York. §Assistant Professor of Neurology, Temple University School of Medicine, Philadelphia, and Neurology Department, Albert Einstein Medical Center Northern Division. !!Assistant Professor of Medicine, Hospital of the University of P~nnsylvania, and Pulmonary Division, the Graduate Hospital, Philadelphia. ,Professor of Medicine, Temple University School of Medicine, Philadelphia, and the Department oflnternal Medicine, Episcopal Hospital. #Associate Professor of Medicine, Temple University School of Medicine, Philadelphia; and Pulmonary Division, Albert Einstein Medical Center Northern Division. Manuscript received February 14; revision accepted August 12. Reprint requem: Dr: Lippmann, Pulmonary Division, Albert Einstein Medical Center, York and Tabor Roads, Philadelphia 19141 238

acute stages of the disease. We report four cases which illustrate the importance of cardiac and respiratory disease in this syndrome.

CASE REPORTS CASE

1

A 51-year-<>ld woman was referred in March 1980, because of chest and abdominal pain of one day's duration. In addition, she also noted numbness and weakness of the legs and hands. On examination, she appeared mildly confused but alert. The pupils were 4 mm in diameter and reacted to light and acCommodation. A coarse horizontal nystagmus was noted on lateral gaze in both directions. Funduscopic examination revealed a sharply demarcated optic disk with no evidence of papilledema, atrophy, or hemorrhage. Slight drooping of the right side of the patients face was noted. Sensation appeared intact to pain and light touch. Corneal reflexes were present bilaterally. Motor examination disclosed mild weakness of distal muscular groups in both the arms and legs. Absent deep-tendon reflexes and dimished sensation to pain and light touch distally were also seen. Bowel and bladder function appeared to be normal, although intermittent urinary incontinence was described. The findings from abdominal examination were unremarkable. The lungs were clear, and there were no murmurs. An electrocardiogram demonstrated sinus rhythm at 68 beats per minute, with frequent ventricular ectopic beats. A chest x-ray film and electrolyte levels were normal. Pulse and blood pressure fluctuated widely, with periods of bradycardia (to 20 beats per minute) and hypotension (to 70/40 mm Hg). Serial ECGs showed Rattening ofT waves, prominent U waves, a prolonged Q-T interval, and frequent ventricular ectopic beats but no evidence of myocardial infarction. There were ten separate episodes of ventricular tachycardia lasting up to 30 seconds. Ventricular ectopy persisted in spite of therapy with lidocaine, procainamide, bretylium sulfate, and propranolol. Continuous electrocardiographic (Holter) monitoring one week after admission showed that 16 percent of all beats were ventricular ectopic beats. A nuclear gated heart scan revealed an ejection fraction of 86 percent, without other abnormality. Over the following weeks, alopecia developed, together with encephalopathy and peripheral neuropathy which led the physicians to screen for drugs and heavy metals. The serum thallium level was SOjLg/100 ml, and the urinary thallium level was 5,000JLg/L. (Thallium was measured in all cases by atomic absorption. The toxic level for serum is greater than 2jLg/100 ml, and urinary level for toxicity is greater than 10jLg/L.) The patient has shown persistent ventricular ectopy (two years after poisoning), partially controlled with procainamide. She remains neurologically disabled, necessitating care in a nursing home. CASE

2

A 45-year-<>ld man had burning pain in his feet, an inability to walk, and alopecia. There was no history of previous medical illness. Physical examination revealed dysarthric speech, poor visual acuity. Cardiopulmonary Effects ol Acute Thallium f"oisonlng (Roby et •J

thy, a choreiform disorder of movement, and blindness. The initial ECG showed sinus tachycardia with Hattened T waves and inverted T waves inferiorly. Subsequent ECGs showed acute atrial fibrillation with rapid ventricular rates, averaging 120 to 150 beats per minute. The patients heart reverted to sinus rhythm after several weeks, and he has been without cardiac symptoms. His peripheral neuropathy has improved so that he is ambulatory with a cane. The patient continues to have severe bilateral visual impairment, with no obtainable responses on visual evoked stimulation. CASE

3

A 61-year-old woman sought emergency evaluation because of retrosternal burning pain in the chest. She had a past medical history only of mild untreated hypertension. The findings from c-ardiac examination and an ECG were normal, and the patient was sent home. On the following day, she returned because of a generalized paresthesia, difficulty in speaking and swallowing, and an inability to walk. On physical examination the patient was stuporous and afebrile, with occasional irregular heart beats. Further history revealed that the patient remembers having ingested a cup of coffee which tasted rather bitter. Vital signs were within normal limits. Cardiac examination demonstrated an s. gallop and a grade-216 systolic murmur at the left sternal border. The patient's speech was slow and her gait severely ataxic. An ECG showed Hattened T waves, prolonged Q-T interval, and atrial ectopic beats. The chest x-ray film taken on admission was normal. An electrodiagnostic study of the peripheral nerves showed an acute axonal sensorimotor neuropathy which prompted a screening for toxic materials, including a heavymetal assay. The serum thallium level was 740JLg/100 mi. No other drug or heavy metal was detected.

FIGURE l. Chest x-ray film (case 3), showing bilateral alveolar infiltrates and normal cardiac size. Note Swan-Ganzcatheter in place in right pulmonary artery outfiow tract. and absent ankle-jerk tendon refiexes. Because of unexplained peripheral neuropathy, the urinary level of thallium \vas measured, which was 2,000JLg/L. Screening for drugs was negative. The patient's course of hospitalization was complicated by encephalopa-

Table 1-Clinical Courses of Cases 3 and 4 Vital Signs

Case and Time Case 311 Admission 48 hr

Arterial Blood Gas Levels*

Blood Pressure, mm Hg

Heart Rate, beats, per min

Res pirations per min

Flo,

PaO,, mmHg

PaC02 , mmHg

120/80 90/60

88 90

20 22

0.21 0.40

73 74

34

80/40 98 16 Dopamine-dependent

0.60 1.00

64 52

49 48

7.24 7.22

39

pH 7.45 7.43

4 days 8 days (died) Case 4~ Admission 10 days 18 days

160/80 170/80 180/80

80 98 70

14 18 32

0.21 0.35

55 127

31 39

7.46 7.22

23 days

250/50

88

20

0.40

149

29

7.40

Chest X-Ray Filmt Normal Bilateral basilar infiltrates ARDS ARDS

Normal Normal Bilateral alveolar infiltrates (ARDS) Bilateral infiltrates and pleural effusions

Pressure, em H 20:!:

Thallium Levels§

PCW

PEEP

Serum

8 15

7.5 12.5

740

422

Urine

21 ,600

12

13

5

*Flo,, Fractional concentration of oxygen in inspired gas. tAROS , Adult respiratory distress syndrome. :I:PCW, Pulmonary capillary wedge pressure; and PEEP. positive end-expiratory pressure. §Serum levels in micrograms per 100 ml; urinary level in micrograms per liter. IIChanges on ECG at four days were atrial arrhythmias and at eight days were T-wave abnormalities. Therapy at four days was activated charcoal and at eight days was ferric ferrocyanate and potassium chloride. ~Changes on ECG at ten days were T-wave inversions. Therapy at ten days was ferric ferrocyanate, dithiocarbonate, potassium chloride, and mechanical ventilation ; at 18 days, tracheostomy was done. CHEST I 85 I 2 I FEBRUARY, 1984

237

Serial chest x-ray films over the first 48 hours of hospitalization showed the development of bilateral alveolar infiltrates, with a normal cardiac size (Fig 1). Arterial blood gas levels showed an increasing alveolar-arterial oxygen tension gradient. On 100 percent inspired oxygen, the arterial oxygen tension (PaOJ was 52 mm Hg. A Swan-Ganz catheter was inserted and revealed a pulmonary arterial pressure ofS0/20 mm Hg and a pulmonary capillary wedge pressure of8 mm Hg, consistent with the clinical diagnosis ofadult respiratory distress syndrome. Thble 1 summarizes the clinical course of this patient. The patient was treated with activated charcoal, ferric ferrocyanide (Prussian blue), potassium supplementation, and mechanical ventilation. Despite these measures, the patient became comatose and died on the seventh day of hospitalization. Postmortem examination of the lungs revealed bilateral pleural effusions, and diffuse interstitial and alveolar in8ammation, with hyaline membrane fOrmation consistent with a diagnosis of the adult respiratory distress syndrome. Cardiac examination showed interstitial edema of the myocardium, disruption of the muscular architecture, and mononuclear infiltrates.

CASE4 An 80-yeaM>Id woman lived in the same house as patient 3. After sharing a meal one week befOre admission, both felt ill, and patient 4 vomited. Over the ensuing week, she noted progressive weakness and paresthesias. Her previous medical history included ischemic heart disease, hypertension, and arthritis. Physical examination revealed an alert elderly woman with normal vital signs and absent lower-extremity and deep-tendon reflexes. Her ECG showed sinus rhythm with . flattened T waves and prominent U waves. Her symptoms and association with patient 3 raised suspicion for thallium poisoning, which was confirmed by a serum thallium level of 422j.~og/100 ml and a urinary thallium level of21, 600j.~og/L. No other drugs were detected. The patients neurologic status declined, with deepening coma and loss of deep-tendon reflexes. One week after admission, alopecia was noted. On the eighth day the patient became dyspneic, with a vital capacity of 300 ml (10 percent of predicted) and an inspiratory force of only -11 em H 10 (normal, more than 25 em H 10), indicating marked weakness of the respiratory muscles. Arterial blood levels demonstrated a Pa01 of 55 mm Hg and an arterial carbon dioxide tension (PaCOJ of 31 mm Hg on room air. A chest x-ray film demonstrated the development of bilateral alveolar edema, with a normal cardiac size, again consistent with the development of the adult respiratory distress syndrome. Mechanical ventilation was Initiated, and the patient was treated with dithiocarbamate, ferric ferrocyanide (Prussian blue), and potassium chloride. The patient remained dependent on a ventilator and died on the 62nd day of hospitalization fOllowing a myocardial infarction. Her case is summarized in Thble 1. The autopsy demonstrated the recent myocardial infarction and bilateral pleural effusions. Thallium was detected in the myocardium. DISCUSSION

Thallium is almost identical to potassium in ionic size and is readily absorbed from the gastrointestinal tract and skin, being then distributed to virtually every organ. The intracellular transfer of thallium is actively facilitated by the sodium-potassium-ATPase pump. Thallium is eliminated from the blood following firstbrder kinetics, with serum half-life varying between 2 and 20 days. 3 •4 The toxic dose in man ranges from 0.2 to 1 g.l.5 The pathogenesis of the toxic effect of thallium is not entirely known; however, this substance is known to 238

interfere with several enzymatic systems, particularly those with reactive sulfhydryl groups.6·7 Thallium also disrupts mitochondria in peripheral nerves and muscle in animals poisoned with thallium. 8 ·9 The cases we report illustrate that cardiac and pulmonary illnesses may dominate the clinical picture of thallium intoxication. Although the incidence of cardiovascular disease in acute thallium intoxication is unknown, all of our cases manifested some cardiac dysfunction. In two cases (ca5es 1 and 2), the cardiac manifestations were the primary non-neurologic problems encountered. Case 1 developed sinus bradycardia and refractory ventricular arrhythmias despite a variety of potent antiarrhythmic drugs. Case 2 had T-wave abnormalities on the ECG and refractory atrial fibrillation. These abnormalities occurred in individuals without a prior history of cardiac disease and are unique because they were the only significant nonneurologic findings present in these patients. The etiology of cardiac disease in acute thallium intoxication is probably multifactorial. Bradycardia has been demonstrated to be a dose-dependent toxic effect of thallium which is not reversed by atropine, suggesting a direct effect on the sinus node. Grunfeld et al10 reported a variety of electrocardiographic abnormalities in rabbits poisoned with massive doses of thallium, including T-wave Battening, prolonged Q-T intervals, heart block, atrial and ventricular ectopic rhythms, and ST-segment depression or elevation. Hughes et al" concluded that the Twave abnormalities observed with thallium intoxication resulted from similarity of thallium to potassium and interference with the sodium-potassium cellular interaction. Several cases of myocardial dysfunction in humans poisoned with thallium have been reported. In 1930, Lynch and Scovell12 described fatty degeneration of the myocardium in two children poisoned with thallium. More recently, Davis et al2 reported electrocardiographic evidence of subendocardial ischemia and infarction in a 19-year-old who ingested massive doses of thallium. Postmortem examination demonstrated extensive myocardial damage with myofibril thinning, accumulation oflipid droplets, and necrosis in association with a sparse inflammatory reaction. In addition, the lungs of this patient showed extensive alveolar damage with hyaline membrane formation consistent with the diagnosis of the adult respiratory distress syndrome. There was no reported measurement of the pulmonary capillary wedge pressure or arterial blood gas levels in this case.2 Thallium was found in very high levels in the myocardium of the left ventricle. Thus, it appears that thallium may interfere both with myocardial muscle and specialized conducting tissues. Pulmonary disease in association with thallium incardiopulmonary Effects ol Acute Thallium Poisoning (Roby eta/)

toxication has only rarely been mentioned in descriptions of this syndrome and has not been specifically detailed. The central and peripheral neurologic disease in case 3 was accompanied by rapid deterioration in her pulmonary function and gas exchange, culminating within the first 24 hours of presentation in the adult respiratory distress syndrome. She was the first person in whom this syndrome has been documented following thallium intoxication. While two other reported cases demonstrated hyaline membranes and interstitial pulmonary inflammation at autopsy, heart failure in those cases was not excluded by Swan-Ganz catheterization. u The pathogenesis of the adult respiratory distress syndrome in this patient is uncertain. The patient was alert and oriented on admission and was not noted to have aspirated at any time during her hospitalization. Pulmonary edema and hemorrhage with alveolar neutrophilic infiltration has been noted in dogs poisoned with thallium. It is presumed that thallium is widely distributed in the body and affects mitochondrial membranes leading to vacuolization within hours of exposure. Thallium may have a direct toxic effect on pulmonary epithelial and endothelial cells, leading to destruction of the alveolar capillary membrane and pulmonary edema. 8 Hence, the adult respiratory distress syndrome. Case 4 had a more subacute pulmonary presentation with peripheral neuropathy and alopecia. The peripheral neurologic and muscular disease eventuated in a neuromuscular respiratory failure, as demonstrated by the patients declining vital capacity and reduced inspiratory force. While thallium intoxication may be confused with the Guillain-Barre syndrome, this is the first case report of neuromuscular induced respiratory failure resulting from this intoxication. Treatment of acute thallium intoxication should be aimed at both gastric and renal elimination of the toxin. Gastric lavage with activated charcoal is often recommended for the immediate removal of the ingested poison. Chelating agents such as dimercaprol (BAL; British Anti-Lewisite), edetic acid (EDTA; Versanate), or diethyldithiocarbamate have been used without any demonstrable success and may actually worsen the situation due to unacceptable renal and pancreatic toxicity. Because the size of the thallium closely matches that of potassium (K + ), potassium chloride has been used effectively to increase excretion by competition with thallium at the renal distal tubule. Several reports indicate favorable responses to therapy with potassium chloride. 4•5 •13 '&eatment with potassium may result in the freeing up of intracellular stores of thallium, thus producing a sudden worsening in neurologic symptoms. This is usually short-lived, but the patient must be observed carefully during therapy. Although there is controversy regarding the efficacy of hemodialysis or peritoneal dialysis, 14•15 most survivors

have received such treatment. As thallium is constantly being recirculated in the body's cells, ferric ferrocyanide (Prussian blue) has been used in the management of these patients. 16•17 This agent blocks the enterohepatic circulation of thallium, thus eliminating the toxin by producing copious diarrhea. None of the available pharmacologic interventions produce an ideal result, thus making routine supportive care of important organ systems the most crucial method of treatment. 18 Forced diuresis, therapy with potassium chloride, and catharsis with ferric ferrocyanide (Prussian blue) may aid in the renal and gastric elimination of this potent toxin. In the case of massive overdose, it is unlikely that any type of therapy will be totally effective. It is difficult to explain the different cardiac and pulmonary manifestations of thallium intoxication in different patients. The lack of associated parasympathetic and sympathetic abnormalities make it unlikely that the cardiac or pulmonary abnormalities were related to a diffuse pandysautonomic state, although autonomic dysfunction has been described in conjunction with thallium intoxication previously. 13•14 In such cases, destruction of the vagus, denervation of the carotid sinus, and lesions of the sympathetic ganglia have been noted. 19 Pathologic examination of peripheral nerve tissue in the postmortem material from case 3 revealed diffuse axonal destruction with extensive wallerian degeneration affecting myelinated as well as unmyelinated nerve fibers . This correlates with toxicologic and morphologic studies of other cases which have demonstrated a central-peripheral type of distal axonopathy. This may account for many of the diverse clinical manifestations of thallotoxicosis, including those involving the lung and heart. 20 In summary, we have reported four cases in which the cardiac and pulmonary manifestations were the primary non-neurologic problems associated with thallium intoxication. Given the findings of unexplained central or peripheral nervous system disease, atrial and ventricular arrhythmias, or rapidly progressing respiratory failure , heavy-metal, especially thallium, intoxication must be considered. ACKNOWLEDGMENT: We thank Dr. Herbert Schaumburg and Dr. Peter Spencer, Albert Einstein Medical Center, Bronx, NY, and Dr. Reed Perron, Ridgewood, NJ, for making case 2 available for inclusion in this report. We also thank Dr. C. A.Fisher, Departments of Biology and Physics, Ursinus College, Collegeville, Pa, and Dr. L. Rorke, Medical Examiner's Office of Philadelphia and Pathology Department, Childrens Hospital, Philadelphia.

REFERENCES 1 Moeschlin S. Poisoning: diagnosis and treatment. New York: Grune and Stratton, 1965:74-93 2 Davis LE, Standefer JC, Kornfeld M, Abercrombie DM, Butler C. Acute thallium poisoning: toxicological and morphological studies of the nervous system. Ann Neurol1981 ; 10:38-44 3 Hologgitas J, Ullucci P, Driscoll J. Thallium elimination kinetics CHEST I 85 I 2 I FEBRUARY, 1984

239

In acute thallotoxicosis. J Anal Toxicol 1980; 44:68-73 4 Lameijer W, Van Wieten PA. Kinetics of thallium elimination in the rat after acute and subacute intoxication: inftuence of diuretic treatment. Proc Eur Soc Toxicol1977; 18:163-5 5 Papp JP, Gay PC, Dodson VN, Pollard MH. Potassium chloride treatment in thallotoxicosis. Ann Intern Med 1969; 71:119-23 6 Hasan M, Chandra SV, Dua PR, Raghubir R, Ali SF. Biochemical and electrophysiologic effects of thallium poisoning on the rat corpus striatum. Toxicol Appl Phannacol1977; 41:353-56 7 Hasan M, Chandra SV, Bajpai VK, Ali SF. Electron microscopic effects of thallium poisoning on the rat hypothalmus and hippocampus: biochemical changes in the cerebrum. Brains Res Bull 1977; 2:255-62 8 Spencer PS, Peterson ER, Madrid R, Raine C. Effects of thallium salts on neuronal mitochondria In organotypic cordganglia-muscle combination cultures. J Cell Biol1973; 58:79-85 9 Deshimaru M, Miyakawa T, Sumiyoshi S, Yasuoka F, Kawano K, Kuramoto M. Electron microscopic study of experimental thallotoxicosis. Folia Psychiat Neurol Jpn 1977; 31:269-75 10 Grunfeld 0, Battilana G, Aldana L, Hinostroza G, Larrea P. Electrocardiographic changes in experimental thallium poisoning. Am J Vet Res 1963; 24:1291-95 11 Hughes MN, Man WK, Whaler BC. The toxicity of thallium to cardiac and skeletal muscle. Chern Bioi Interact 1978; 23:85-90

240

12 Lynch GR, Scovell JMS. The toxicology of thallium. Lancet 1930; 1:1340-42 13 Bank WJ, Pleasure DE, Suzuki K, Nigro M, Katz R. Thallium poisoning. Arch Neurol1972; 26:456-69 14 Moses H. Thallium poisoning. Johns Hopkins Med J 1978; 142:27-31 15 Pedersen RS, Anders SO, Freund LG, Solgaard P, Larsen E. Thallium intoxication treated with long-term hemodialysis, fOrced diuresis and Prussian blue. Acta Med Scand 1978;

204:429-32 16 Cavanagh JB, Fuller NH, Johnson HRM, Rudge P. The effects of thallium salts, with particular reference to the nervous system changes. Q J Med 1974; 58:293-319 17 Karnerbeck H, Rauws AG, ten Ham M, van Heigst ANP. Prussian blue therapy of thallotoxicosis. Acta Med Scand 1971; 189:321-24 18 Grunfeld 0, Hinostroza G. Thallium poisoning. Arch Intern Med 1964; 114:132-38 19 Prick JJG. Thallium poisoning. In: Vinken PJ, Bruyn GW, eds. Handbook of clinical neurology. vol 36. Amsterdam: North Holland Publishing Co, 1979; 239-78 20 Davis LE, Stadelfeler JC, Kornfeld M, Abercrombie DM, Butler C. Acute thallium poisoning: toxicological and morphological studies of the nervous system. Ann Neurol1981; 16:38-42