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Acute Pulmonary Edema Induced by Overdosage of Phenothiazines

1992; Elsevier BV; Volume: 101; Issue: 1 Linguagem: Inglês

10.1378/chest.101.1.102

1931-3543

Cheng Li, Warren B. Gefter,

Pharmacological Receptor Mechanisms and Effects

Three schizophrenic adults with previous histories of using phenothiazine derivatives developed acute pulmonary edema after taking large amounts of these drugs. The clinical manifestations included coma (three), hypothermia (two), tachycardia (two), miosis (two) and hypotension (one). All three patients underwent gastric lavage and were treated supportively. The fulminant pulmonary edema in the three cases resolved within 18 to 40 h. The etiology of pulmonary edema following overdosage of phenothiazines remains unknown. The authors hypothesize that the most likely pathogenesis is a drug-induced neurogenic pulmonary edema resulting from a disturbance of hypothalamic function. Three schizophrenic adults with previous histories of using phenothiazine derivatives developed acute pulmonary edema after taking large amounts of these drugs. The clinical manifestations included coma (three), hypothermia (two), tachycardia (two), miosis (two) and hypotension (one). All three patients underwent gastric lavage and were treated supportively. The fulminant pulmonary edema in the three cases resolved within 18 to 40 h. The etiology of pulmonary edema following overdosage of phenothiazines remains unknown. The authors hypothesize that the most likely pathogenesis is a drug-induced neurogenic pulmonary edema resulting from a disturbance of hypothalamic function. A cute pulmonary edema may be caused by ingestion of opiate derivatives, sedatives, or tranquilizers. Common potential drugs include heroin, morphine, methadone, propoxyphen, barbiturates, and tricyclic antidepressants.1Gefter WB Drug-induced disorders of the chest.in: Taveras TM Ferrucci JT Radiology. Lippincott Co, Philadelphia1987Google Scholar, 2Cooper JAD White DA Matthay RA Drug-induced pulmonary disease: Part 2. Noncytotoxic drugs.Am Rev Respir Dis. 1986; Google Scholar, 3Mahutte CK Nakasato SK Light RW Haloperidol and sudden death due to pulmonary edema.Arch Intern Med. 1982; 142: 1951-1952Crossref PubMed Scopus (21) Google Scholar, 4Vannell RM Godwin JD Richardson ML Vincent JM Adult respiratory distress syndrome from overdose of tricyctic antidepressants.Radiology. 1989; 170: 667-670Crossref Scopus (31) Google Scholar Neuroleptic agents, such as phenothiazines, butyrophenones, and thioxanthenes, may occasionally cause neuroleptic malignant syndrome.3Mahutte CK Nakasato SK Light RW Haloperidol and sudden death due to pulmonary edema.Arch Intern Med. 1982; 142: 1951-1952Crossref PubMed Scopus (21) Google Scholar, 5Smego Jr, RA Durack DT The neuroleptic malignant syndrome.Arch Intern Med. 1982; 142: 1183-1185Crossref PubMed Scopus (112) Google Scholar, 6Henderson VW Wooten GF Neuroleptic malignant syndrome: a pathogenetic role for dopamine receptor blockade?.Neurology. 1981; 31: 132-137Crossref PubMed Google Scholar, 7Morris HH McCormick WF Reinarz JA Neuroleptic malignant syndrome.Arch Neurol. 1980; 37: 462-463Crossref PubMed Scopus (54) Google Scholar The striking clinical characteristics of the neuroleptic malignant syndrome are hyperthermia, diaphoresis, hypertonicity, disorder of consciousness, tachycardia, and respiratory insufficiency. We encountered three cases of acute pulmonary edema following an overdosage of phenothiazines, two cases from chlorpromazine and one from perphenazine. The typical features of the neuroleptic malignant syndrome were absent in each of these cases. To our knowledge, phenothiazine-induced pulmonary edema has not been previously described. Potential mechanisms underlying this drug reaction are discussed, and a central neurogenic cause of the pulmonary edema is hypothesized. A 24-year-old schizophrenic man was brought to the emergency room by his parents in coma of 2 h duration after ingestion of about 180 tablets of chlorpromazine (25 mg per tablet, total about 4,500 mg). The patient had a diagnosis of paranoid schizophrenia since 19 years of age, for which he had been taking about 150 mg of chlorpromazine daily. Physical examination on admission revealed that the patient was comatose, unresponsive to stimuli. Blood pressure was 80/60 mm Hg (supine position). Pulse was 104 beats per minute; respiratory rate was 15 per minute, and temperature was 35°C. Gastric lavage was immediately performed. An arterial blood gas analysis with the patient breathing ambient air showed pH of 7.26; PO2, 33 mm Hg; PCO2, 46.8 mm Hg. The patients pupils were constricted equally and unresponsive to light. Auscultation of the lungs revealed diffuse rales over both lung fields, especially at the bases. White blood cell count was 8,800/cu mm with 78 percent polymorphonuclear cells and 22 percent lymphocytes. Serum electrolyte studies showed a serum sodium value of 140 mEq/L; potassium level, 3.4 mEq/L; and chloride value, 106 mEq/L. Liver and kidney functions were normal. Electrocardiogram showed sinoatrial rhythm, sinus tachycardia, and slight ST depression. A portable anteroposterior chest roentgenogram revealed both interstitial and alveolar opacities bilaterally and a normal size heart. (Fig 1, left) The clinical diagnosis was that of coma with acute pulmonary edema caused by overdosage of chlorpromazine. The patient was treated with oxygen, intravenous administration of fluid, vitamin C, 15 percent potassium chloride, methylphenidate hydrochloride, metaraminol bitartrate, and antibiotics. About 7 h later, the patient gradually regained consciousness. A chest radiograph after 18 h revealed that the acute pulmonary edema had completely resolved (Fig 1, right) Repeat blood gas values were normal. Case 2 and 3 are summarized in Table 1 (Fig 2).Table 1Case HistoriesCase 1Case 2Case 3Age, Sex24, Male32, Female48, FemaleBackground of patientParanoid schizophrenia for 5 years. 150 mg chlorpromazine orally daily to prevent onset of diseaseTen year history of schizophrenia with about 100 mg chlorpromazine orally every daySix-year history of schizophrenia. Five to six perphenazine tablets (10-12 mg) per dayDrug dosageIngestion of about 4,500 mg chlorpromazine once≥2,000 mg chlorpromazine once, orally, (80 to 100 tablets 25 mg chlorpromazine)Swallowing 100 2 mg tablets of perphenazine (total about 200 mg)Onset after ingestion Major clinic manifestation on admission30 minComa, hypothermia, hypotension, tachycardia miosis30 min Coma60 minComa, hypothermia, tachycardia, miosisBlood gases on admissionpH 7.26, PO2 33 mm Hg, PCO2 46.8 mm HgpH 7.38, PO2 44 mm Hg, PCO2 35 mm HgpH 7.35, PO2 42 mm Hg, PCO2 36 mm HgOther laboratory dataBlood cell counts, electrolytes, kidney & liver function all within normal limitsNormalNormalElectrocardiogramSinoatrial rhythm, sinus tachycardia & slight ST depressionNormalMild sinus tachycardiaChest radiographBilat diffuse, pulmonary opacities. The size & contour of the heart is normal (Fig 1, left)Diffuse, poorly defined infiltrates throughout both lungs with decreased lung volumes. Cardiac shadow is normal.Bilat pulmonary opacities with decreased lung volumes. Cardiac shadow is normal. (Fig 2)TherapyGastric lavage, oxygen, IV fluid, vitamin C, KCl, methylphenidate, metaraminol, antibioticsGastric lavage, oxygen, IV fluid, antibioticsGastric lavage, oxygen, IV fluidOutcome7 h after admission patient regained consciousness; 18 h later, acute pulmonary edema completely resolved. (Fig 1, right)24 h after admission patient completely recovered. Acute pulmonary edema cleared.About 4 h after admission patient gradually regained consciousness. Chest x-ray taken 40 h after admission was normal. Open table in a new tab At least 30 different drugs have been reported to cause pulmonary edema.1Gefter WB Drug-induced disorders of the chest.in: Taveras TM Ferrucci JT Radiology. Lippincott Co, Philadelphia1987Google Scholar, 2Cooper JAD White DA Matthay RA Drug-induced pulmonary disease: Part 2. Noncytotoxic drugs.Am Rev Respir Dis. 1986; Google Scholar, 4Vannell RM Godwin JD Richardson ML Vincent JM Adult respiratory distress syndrome from overdose of tricyctic antidepressants.Radiology. 1989; 170: 667-670Crossref Scopus (31) Google Scholar The pathogenesis of phenothiazine-induced pulmonary edema, currently unknown, might be similar to that of pulmonary edema caused by overdosage of heroin or methadone.9Theodore J Robin ED Speculations on neurogenic pulmonary edema.Am Rev Respir Dis. 1976; 113: 405-411PubMed Google Scholar, 10Wilen SB Ulreich S Rabinowitz JG Roentgenographic manifestations of methadone-induced pulmonary edema.Radiology. 1975; 114: 51-55Crossref Scopus (12) Google Scholar Central neurogenic disturbances by the offending drugs likely play a principal role, as the phenothiazines exert their basic therapeutic and adverse effects through dopamine-receptor blockade in the basal ganglia and hypothalamus.6Henderson VW Wooten GF Neuroleptic malignant syndrome: a pathogenetic role for dopamine receptor blockade?.Neurology. 1981; 31: 132-137Crossref PubMed Google Scholar, 8AHFS. Drug Information. 1988:1158-63Google Scholar There is evidence to indicate that phenothiazines antagonize dopamine-mediated neurotransmission at the synapses. The effects of phenothiazines on the autonomic nervous system are complex and unpredictable, since the drugs exhibit varying degrees of alpha-adrenergic blocking, muscarinic blocking and adrenergic activity.8AHFS. Drug Information. 1988:1158-63Google Scholar In contrast to the typical cases of neuroleptic malignant syndrome, the present cases showed fulminent pulmonary edema and coma without hyperthermia and muscular rigidity. These manifestations may well be secondary to depression and biochemical dysfunction of the hypothalamus by the heavy dosage of the offending drugs. Of course, hypoxemia and cardiovascular complications could accelerate the process. While central venous pressures were not measured, left ventricular failure as a cause for the edema was not likely, as the edema cleared despite the administration of intravenous fluids. In addition, the heart sizes and contours on the portable chest films were normal. The cardiovascular effects of phenothiazines are complex, the most common phenomena being tachycardia, orthostatic hypotension, and electrocardiographic changes.8AHFS. Drug Information. 1988:1158-63Google Scholar, 11Raj MVJ Benson R Phenothiazines and the electrocardiogram.Postgrad Med J. 1975; 51: 65-68Crossref Scopus (10) Google Scholar Indeed, there was sinus tachycardia, slight ST depression on ECG, and hypotension in case 1. However, the electrocardiograms in the remaining two cases were essentially normal. Direct toxicity of the offending agents on the pulmonary capillary membranes leading to a capillary permeability edema is also unlikely, given the rapidity of resolution of the pulmonary edema in these cases over 18 to 40 h. Included in the differential diagnosis of the diffuse pulmonary infiltrates in these cases are drug hypersensitivity, gastric aspiration, and pneumonia. All of the three cases had been using phenothiazines chronically for years, without any skin rash or allergic reactions. The sudden changes, therefore, were not likely to be caused by drug hypersensitivity. None of the patients had blood eosinophilia. Because the three cases had undergone gastric lavage in the emergency room, the possibility of aspiration of gastric contents may be considered. Landay and his colleagues,13Landay MJ Christenson EE Bynum LJ Pulmonary manifestations of acute aspiration of gastric contents.AJR. 1978; 131: 587-592Crossref PubMed Scopus (36) Google Scholar in a review of 60 such cases, noted that roentgenographic changes often worsen for several days in uncomplicated cases, but improvement is generally manifested within the first week after aspiration. Most patients also develop fever. In contrast, the three patients reported here were afebrile, and the pulmonary infiltrates cleared rapidly. Chlorpromazine and perphenazine, both phenothiazine derivatives, are widely used in the management of psychotic conditions. The diagnosis of phenothiazine-induced pulmonary edema should be suspected in any patient with potential access to these drugs who presents with coma and diffuse pulmonary infiltrates. The treatment, apart from withdrawal of the offending agent, is essentially supportive.