Codeine-Induced Pulmonary Edema* Joel Sklar, M.D.;•• and Richard M. Timms, M.D., F.C.C.P.t
We recently treated a patient with pulmonary edema and an oral overdose of codeine. Although overdoses of other opiate drugs are known to cause pulmonary edema, the association of an overdose of codeine with pulmooary edema has not been reported previously.
T
he association of an overdose of an opiate drug with pulmonary edema is well established. Heroin, methadone, and analogues, including propoxyphene, have been implicated in this syndrome by intravenous injection, oral ingestion, and nasal inhalation ("snorting") .1 4 We recently treated a victim of drug overdose causing pulmonary edema who by history and laboratory analysis had ingested only codeine. To our knowledge, this association has not been reported previously. CASE REPORT
A 21-year-old previously healthy white man was taken to an outlying hospital emergency room because of a drug overdose at a party. He arrived there in a coma, with tachypnea and normal blood pressure. Analysis of arterial blood gas levels with the patient breathing room air showed: arterial oxygen pressure ( Pa02) of 34 mm Hg, arterial carbon dioxide tension (PaC02) of 46 mm Hg, and pH of 7.33. The chest x-ray film showed a hazy infiltrate in the right lower lobe. The patient was treated unsuccessfully with naloxone and then was intubated; two hours after arrival in the emergency room, he was transferred to University Hospital., The patient's friends (and later he himself) denied the Use of heroin or any intravenous administration of drugs, but he admitted talcing a large number of codeine tablets orally. Codeine tablets were found in his poclcets. Physical examination on admission revealed that the patient was lethargic, but agitated, with shallow, rapid spontaneous respirations at a rate of 30/min. The pulse rate was 100 beats per minute and regular. The blood pressure was 130/80 mm, Hg with the patient supine, and the rectal temperature was 37.4•C. (99.3•F) . The skin was clammy, and there were fresh needle marks in both antecubital fossae but no old needle tracks (venipunctures had been performed at the referring hospital). An endotracheal tube was in place. There was no evidence of trauma. Pupils measured 3 mm bilaterally and were reactive. The jugular venous pressure was estimated at 5 em H20. There were diffuse rhonchi over both pulmonary fields. The heart and abdomen were normal. There were well-healed operative scars from a recent repair of a fractured right tibia. The patient was lethargic but able to respond to simple commands, and findings from the remainder of the neurologic examination were normal. The hematocrit reading was 37 percent, with a white blood cell count of 12,600/cu mm (f)[ percent segmented forms, 22 percent band cells, 4 percent lymphocytes, and 6 percent °From the Department of Medicine, University Hospital, San Diego, California. Resident in Medicine. t Assistant Professor of Medicine.
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230 SKLAR, TIMMS
monocytes) . Other laboratory values were as follows : blood urea nitrogen, 21 mg/100 ml; serum creatinine 1.5 mg/100 ml; serum sodium, 144 mEq/L; serum chloride, 103 mEq/L; bicarbonate, 24 mEq/L; glucose, 136 mg/100 ml; serum glutamic oxaloactic transaminase, 36 international units ( IU ) per liter; and lactic dehydrogenase, 211 IU/L. Toxicologic screening performed on admission revealed codeine in the serum and aspirin in the urine. Other opiates, barbiturates, propoxyphene, and alcohol were specifically absent. There were no measurable serum levels of salicylates, and a quantitative level of codeine was not obtained. An electrocardiogram showed sinus tachycardia. The chest x-ray film taken two hours after his initial appearance at the emergency room ( Fig 1 ) showed patchy bilateral infiltrates compatible with pulmonary edema. The cardiac silhouette was normal. The results of urinalysis were normal. Analysis of arterial blood gas levels with the patient breathing a fractional concentration of oxygen in the inspired gas ( FI02) of 0.40 via endotracheal tube showed a Pa02 of 40 mm Hg, a PaC~ of 43 mm Hg, and a pH of 7.41. With an FI02 of 0.60, the Pa02 was 65 mm Hg, the PaC~ was 36 mm Hg, and the pH was 7.45. The patient was admitted to the medical intensive care unit, where he did not require mechanical ventilation. By the next morning, he was fully alert and was extubated. Treatment with penicillin, chest physiotherapy, and oxygen by maslc was continued. Twenty-four hours after admission, the chest x-ray film showed almost complete resolution. By 48 hours, analysis of arterial blood gas levels with the patient breathing room air showed a Pa02 of 89 mm Hg, a PaC02 of 37 mm Hg, and a pH of 7.42. He recovered without further complications and was discharged on the third day of hospitalization. DISCUSSION
The clinical and roentgenographic course of this patient fit the pattern of the "heroin lung." He had taken an overdose of narcotic and within two hours of the overdose had pulmonary edema requiring supplemental oxygen, although not assisted ventilation. Toxicologic studies confirmed the presence of codeine in the serum. Twenty-four hours later, the patient was alert and ex-
FlcURE 1. Portable anteroposterior chest x-ray film taken on admission to University Hospital (June 7, 1975) .
CHEST, 72: 2, AUGUST, 1977
tubated, and had a virtuaJly clear chest x-ray fihn . By 48 hours, he was discharged. Previous reports have documented a clinical course of heroin-induced pulmonary edema which is similar to that of our patient. The pulmonary edema may occur abruptly or as long as eight to ten hours after injection or ingestion. The edema may first appear tmilaterally, as in our patient, or bilaterally. 1 The spread and subsequent resolution of the edema are usually rapid, with nearly complete clinical recovery in two to three days. Subtle abnormalities of pulmonary function may not resolve for several months, if at all.•-e When this patient was initially seen, his clinical appearance was primarily that of narcotic depression, and he had not yet developed definite roentgenographic evidence of pulmonary edema. By the time he was transferred to our hospital, the physical signs of pulmonary edema and hypoxemia overshadowed those of this resolving overdose, and his chest x-ray 6hn showed bilateral infiltrates. A number of patients have been reported in whom the partial resolution of coma preceded the development of frank pulmonary edema.• Most patients are comatose and hypoxemic at some time during their clinical course, as was this patient. Overdoses of heroin, methadone, propoxyphene, and other narcotics have caused pulmonary edema, t-3 so it is not surprising to find pulmonary edema associated with an overdose of codeine. Codeine is not one of the narcotics with a higher potential for abuse, 7 but given the widespread use of the drug, it is surprising that overdoses associated with pulmonary edema have not been observed more frequently. In one report of a fatal overdose from a codeine-containing cough syrup, "engorged lungs," as well as cerebral edema, were reported in a 21year-old patient at necropsy,8 but we are not aware of any other documented association. The pathogenesis and possible mechanisrils of narcotic-induced pulmonary edema recently have been discussed. 9 - 11 The pathophysiology is based on an increased permeability of the walls of the pulmonary capillaries, leading to the formation of an edematous fluid high in protein content.12 Whether initially there was postcapillary venoconstriction is unclear, but pulmonary arterial wedge pressures have been normal when measured. 9 There is suggestive, but not conclusive, evidence implicating neurogenic, 11 toxic, 6 and hypoxic13 insults as the primary event producing the vascular changes, but the relative contribution (if any) of these factors remains unknown. Cardiac depression may be associated with the syndrome14 but does not commonly play a role in the pathogenesis of the pulmonary edema. Allergy and "constitutional susceptibility" to either the drugs or contaminants are less likely pathogenetic factors. •·9 Treatment of narcotic-induced pulmonary edema, as in the present case, is supportive. Naloxone is given to counteract the depressant effects of the narcotic. Supplemental oxygen and mechanical ventilation are often necessary. Aspiration is usually suspected, and the susceptibility of patients with narcotic-induced pulmonary edema to bacterial pneumonia has been recognized. H Therapy with antibiotics and corticosteroids has been rec-
CHEST, 72: 2, AUGUST, 1977
ommended, but the benefits of prophylactic treatment are unproven.• Diuretic drugs may be of value. 8 Digitalis is not warranted, except in unusual cases when cardiac dysfunction is part of the syndrome. 10 •15• 16 Right cardiac catheterization with recording of wedge pressure may be necessary to delineate such cases. Delay in recovery of consciousness suggests other involvement of the central nervous system, such as anoxic damage. Delay in resolution of pulmonary abnormalities suggests pneumonia, aspiration, or underlying cardiac or pulmonary disease. ACKNOWLEDGMENTS: .We thank Dr. J. S. Karliner for his helpful criticism and advice.
1 Wilen SB, Ulreich S, Rabinowitz JG: Roentgenographic manifestations of methadone induced pulmonary edema. Radiology 114:51-55, 1975 2 Osler W: Oedema of left lung: Morphine poisoning. Montreal Gen Hosp Rep 1:291-292, 1898 3 Bogartl; LJ, Miller WC: Pulmonary edema associated with propxyphene intoxication. JAMA 215:259-262, 1971 4 Steinberg AD, Karliner JS : The clinical spectrum of heroin pulmonary edema. Arch Intern Med 122:122-127, 1968 5 Karliner JS, Steinberg AD, Williams MH: Lung function after pulmonary edema associated with heroin overdose. Arch Intern Med 124:350-353, 1969 6 Frand Ul, Chang SS, Williams MH: Heroin induced pulmonary edema. Ann Intern Med 77:29-35, 1972 7 Goodman LS, Gilman A: The Pharmacological Basis of Therapeutics. New York, Macmillan Co, 1970 8 Winek CL, Collam VD, Wecht CH: Codeine fatality from cough syrup. Clin Toxicol3:97-100, 1970 9 Robin ED, C~oss CE, Zelis R: Pulmonary edema. N Engl J Med 288:292-304, 1973 10 Staub NC : Pathogenesis of pulmonary edema. Am Rev Respir Dis 109:358-372, 1974 11 Theodore J, Robin ED: Speculations on neurogenic pulmonary edema. Am Rev Respir Dis 113:405-411, 1976 12 Katz S, Aberman A, Frand Ul, et al: Heroin pulmonary edema: Evidence for increased pulmonary capillary permeability. Am Rev Respir Dis 106:472-474, 1972 13 Moss C: Shock lung: A disorder of the central nervous system? Hosp Prac, (August) 1974, pp 77-86 14 Duberstein JL, Kaufman DM : A clinical study of heroin intoxication and heroin-induced pulmonary edema. Am J Med 51:704-714, 1971 15 Paranthaman SK, Khan F : Acute cardiomyopathy with recurrent pulmonary edema and hypotension following heroin overdosage. Chest 69 :117-119, 1976 16 Levine SB, Grimes ET : Pulmonary edema and heroin overdose in Vietnam. Arch Pathol95:330-332, 1973
CODEINE-INDUCED PULMONARY EDEMA 231
We recently treated a patient with pulmonary edema and an oral overdose of codeine. Although overdoses of other opiate drugs are known to cause pulmonary edema, the association of an overdose of codeine with pulmooary edema has not been reported previously.
T
he association of an overdose of an opiate drug with pulmonary edema is well established. Heroin, methadone, and analogues, including propoxyphene, have been implicated in this syndrome by intravenous injection, oral ingestion, and nasal inhalation ("snorting") .1 4 We recently treated a victim of drug overdose causing pulmonary edema who by history and laboratory analysis had ingested only codeine. To our knowledge, this association has not been reported previously. CASE REPORT
A 21-year-old previously healthy white man was taken to an outlying hospital emergency room because of a drug overdose at a party. He arrived there in a coma, with tachypnea and normal blood pressure. Analysis of arterial blood gas levels with the patient breathing room air showed: arterial oxygen pressure ( Pa02) of 34 mm Hg, arterial carbon dioxide tension (PaC02) of 46 mm Hg, and pH of 7.33. The chest x-ray film showed a hazy infiltrate in the right lower lobe. The patient was treated unsuccessfully with naloxone and then was intubated; two hours after arrival in the emergency room, he was transferred to University Hospital., The patient's friends (and later he himself) denied the Use of heroin or any intravenous administration of drugs, but he admitted talcing a large number of codeine tablets orally. Codeine tablets were found in his poclcets. Physical examination on admission revealed that the patient was lethargic, but agitated, with shallow, rapid spontaneous respirations at a rate of 30/min. The pulse rate was 100 beats per minute and regular. The blood pressure was 130/80 mm, Hg with the patient supine, and the rectal temperature was 37.4•C. (99.3•F) . The skin was clammy, and there were fresh needle marks in both antecubital fossae but no old needle tracks (venipunctures had been performed at the referring hospital). An endotracheal tube was in place. There was no evidence of trauma. Pupils measured 3 mm bilaterally and were reactive. The jugular venous pressure was estimated at 5 em H20. There were diffuse rhonchi over both pulmonary fields. The heart and abdomen were normal. There were well-healed operative scars from a recent repair of a fractured right tibia. The patient was lethargic but able to respond to simple commands, and findings from the remainder of the neurologic examination were normal. The hematocrit reading was 37 percent, with a white blood cell count of 12,600/cu mm (f)[ percent segmented forms, 22 percent band cells, 4 percent lymphocytes, and 6 percent °From the Department of Medicine, University Hospital, San Diego, California. Resident in Medicine. t Assistant Professor of Medicine.
0 0
230 SKLAR, TIMMS
monocytes) . Other laboratory values were as follows : blood urea nitrogen, 21 mg/100 ml; serum creatinine 1.5 mg/100 ml; serum sodium, 144 mEq/L; serum chloride, 103 mEq/L; bicarbonate, 24 mEq/L; glucose, 136 mg/100 ml; serum glutamic oxaloactic transaminase, 36 international units ( IU ) per liter; and lactic dehydrogenase, 211 IU/L. Toxicologic screening performed on admission revealed codeine in the serum and aspirin in the urine. Other opiates, barbiturates, propoxyphene, and alcohol were specifically absent. There were no measurable serum levels of salicylates, and a quantitative level of codeine was not obtained. An electrocardiogram showed sinus tachycardia. The chest x-ray film taken two hours after his initial appearance at the emergency room ( Fig 1 ) showed patchy bilateral infiltrates compatible with pulmonary edema. The cardiac silhouette was normal. The results of urinalysis were normal. Analysis of arterial blood gas levels with the patient breathing a fractional concentration of oxygen in the inspired gas ( FI02) of 0.40 via endotracheal tube showed a Pa02 of 40 mm Hg, a PaC~ of 43 mm Hg, and a pH of 7.41. With an FI02 of 0.60, the Pa02 was 65 mm Hg, the PaC~ was 36 mm Hg, and the pH was 7.45. The patient was admitted to the medical intensive care unit, where he did not require mechanical ventilation. By the next morning, he was fully alert and was extubated. Treatment with penicillin, chest physiotherapy, and oxygen by maslc was continued. Twenty-four hours after admission, the chest x-ray film showed almost complete resolution. By 48 hours, analysis of arterial blood gas levels with the patient breathing room air showed a Pa02 of 89 mm Hg, a PaC02 of 37 mm Hg, and a pH of 7.42. He recovered without further complications and was discharged on the third day of hospitalization. DISCUSSION
The clinical and roentgenographic course of this patient fit the pattern of the "heroin lung." He had taken an overdose of narcotic and within two hours of the overdose had pulmonary edema requiring supplemental oxygen, although not assisted ventilation. Toxicologic studies confirmed the presence of codeine in the serum. Twenty-four hours later, the patient was alert and ex-
FlcURE 1. Portable anteroposterior chest x-ray film taken on admission to University Hospital (June 7, 1975) .
CHEST, 72: 2, AUGUST, 1977
tubated, and had a virtuaJly clear chest x-ray fihn . By 48 hours, he was discharged. Previous reports have documented a clinical course of heroin-induced pulmonary edema which is similar to that of our patient. The pulmonary edema may occur abruptly or as long as eight to ten hours after injection or ingestion. The edema may first appear tmilaterally, as in our patient, or bilaterally. 1 The spread and subsequent resolution of the edema are usually rapid, with nearly complete clinical recovery in two to three days. Subtle abnormalities of pulmonary function may not resolve for several months, if at all.•-e When this patient was initially seen, his clinical appearance was primarily that of narcotic depression, and he had not yet developed definite roentgenographic evidence of pulmonary edema. By the time he was transferred to our hospital, the physical signs of pulmonary edema and hypoxemia overshadowed those of this resolving overdose, and his chest x-ray 6hn showed bilateral infiltrates. A number of patients have been reported in whom the partial resolution of coma preceded the development of frank pulmonary edema.• Most patients are comatose and hypoxemic at some time during their clinical course, as was this patient. Overdoses of heroin, methadone, propoxyphene, and other narcotics have caused pulmonary edema, t-3 so it is not surprising to find pulmonary edema associated with an overdose of codeine. Codeine is not one of the narcotics with a higher potential for abuse, 7 but given the widespread use of the drug, it is surprising that overdoses associated with pulmonary edema have not been observed more frequently. In one report of a fatal overdose from a codeine-containing cough syrup, "engorged lungs," as well as cerebral edema, were reported in a 21year-old patient at necropsy,8 but we are not aware of any other documented association. The pathogenesis and possible mechanisrils of narcotic-induced pulmonary edema recently have been discussed. 9 - 11 The pathophysiology is based on an increased permeability of the walls of the pulmonary capillaries, leading to the formation of an edematous fluid high in protein content.12 Whether initially there was postcapillary venoconstriction is unclear, but pulmonary arterial wedge pressures have been normal when measured. 9 There is suggestive, but not conclusive, evidence implicating neurogenic, 11 toxic, 6 and hypoxic13 insults as the primary event producing the vascular changes, but the relative contribution (if any) of these factors remains unknown. Cardiac depression may be associated with the syndrome14 but does not commonly play a role in the pathogenesis of the pulmonary edema. Allergy and "constitutional susceptibility" to either the drugs or contaminants are less likely pathogenetic factors. •·9 Treatment of narcotic-induced pulmonary edema, as in the present case, is supportive. Naloxone is given to counteract the depressant effects of the narcotic. Supplemental oxygen and mechanical ventilation are often necessary. Aspiration is usually suspected, and the susceptibility of patients with narcotic-induced pulmonary edema to bacterial pneumonia has been recognized. H Therapy with antibiotics and corticosteroids has been rec-
CHEST, 72: 2, AUGUST, 1977
ommended, but the benefits of prophylactic treatment are unproven.• Diuretic drugs may be of value. 8 Digitalis is not warranted, except in unusual cases when cardiac dysfunction is part of the syndrome. 10 •15• 16 Right cardiac catheterization with recording of wedge pressure may be necessary to delineate such cases. Delay in recovery of consciousness suggests other involvement of the central nervous system, such as anoxic damage. Delay in resolution of pulmonary abnormalities suggests pneumonia, aspiration, or underlying cardiac or pulmonary disease. ACKNOWLEDGMENTS: .We thank Dr. J. S. Karliner for his helpful criticism and advice.
1 Wilen SB, Ulreich S, Rabinowitz JG: Roentgenographic manifestations of methadone induced pulmonary edema. Radiology 114:51-55, 1975 2 Osler W: Oedema of left lung: Morphine poisoning. Montreal Gen Hosp Rep 1:291-292, 1898 3 Bogartl; LJ, Miller WC: Pulmonary edema associated with propxyphene intoxication. JAMA 215:259-262, 1971 4 Steinberg AD, Karliner JS : The clinical spectrum of heroin pulmonary edema. Arch Intern Med 122:122-127, 1968 5 Karliner JS, Steinberg AD, Williams MH: Lung function after pulmonary edema associated with heroin overdose. Arch Intern Med 124:350-353, 1969 6 Frand Ul, Chang SS, Williams MH: Heroin induced pulmonary edema. Ann Intern Med 77:29-35, 1972 7 Goodman LS, Gilman A: The Pharmacological Basis of Therapeutics. New York, Macmillan Co, 1970 8 Winek CL, Collam VD, Wecht CH: Codeine fatality from cough syrup. Clin Toxicol3:97-100, 1970 9 Robin ED, C~oss CE, Zelis R: Pulmonary edema. N Engl J Med 288:292-304, 1973 10 Staub NC : Pathogenesis of pulmonary edema. Am Rev Respir Dis 109:358-372, 1974 11 Theodore J, Robin ED: Speculations on neurogenic pulmonary edema. Am Rev Respir Dis 113:405-411, 1976 12 Katz S, Aberman A, Frand Ul, et al: Heroin pulmonary edema: Evidence for increased pulmonary capillary permeability. Am Rev Respir Dis 106:472-474, 1972 13 Moss C: Shock lung: A disorder of the central nervous system? Hosp Prac, (August) 1974, pp 77-86 14 Duberstein JL, Kaufman DM : A clinical study of heroin intoxication and heroin-induced pulmonary edema. Am J Med 51:704-714, 1971 15 Paranthaman SK, Khan F : Acute cardiomyopathy with recurrent pulmonary edema and hypotension following heroin overdosage. Chest 69 :117-119, 1976 16 Levine SB, Grimes ET : Pulmonary edema and heroin overdose in Vietnam. Arch Pathol95:330-332, 1973
CODEINE-INDUCED PULMONARY EDEMA 231
