An Unresponsive Biochemistry Professor in the Bathtub

pulmonary and critical care pearls An Unresponsive Biochemistry Professor in the Bathtub* Go¨khan M. Mutlu, MD, FCCP; Jerrold B. Leikin, MD; Kyong Oh, MD; and Phillip Factor, DO, FCCP

(CHEST 2002; 122:1073–1076)

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n 83-year-old retired biochemistry professor was found by his wife unresponsive in his bathtub approximately 60 min after their last conversation. She found him lying upright in the empty bathtub, wearing pajamas with his arms folded across his chest. When emergency medical services arrived, he was hypopneic, with a barely palpable pulse and no measurable BP. En route to the hospital, pulseless electrical activity developed for which he received chest compressions, IV epinephrine (1 mg) and atropine (1 mg), with return of spontaneous circulation after ⬍ 10 min of resuscitation. The patient’s medical history was notable for ischemic cardiomyopathy and a recent stroke that diminished his functional capacity, although he remained able to perform most activities of daily life. Physical Examination Initial physical examination in the emergency department (ED) revealed an elderly man with a weak, irregular pulse but no measurable BP. There were no spontaneous respirations. He was hypothermic (32.8°C) and had mydriasis with no response to light. His oropharynx held no foreign body, and his mucosa was pink. There were no signs of head trauma. Laboratory and Radiographic Findings

A 12-lead ECG showed atrial fibrillation (ventricular rate of 72/min), with 1- to 2-mm ST-segment depression in leads V4 through V6. Cardiac enzymes were elevated: myoglobin level was ⬎ 900 ng/mL (normal range, 21 to 98 ng/mL), creatine kinase-MB *From the Department of Medicine (Dr. Oh), Division of Pulmonary and Critical Care Medicine (Drs. Factor and Mutlu), and Medical Toxicology (Dr. Leikin), Evanston Northwestern Healthcare, Evanston, IL. Manuscript received November 26, 2001; revision accepted January 24, 2002. Correspondence to: Go¨khan M. Mutlu, MD, FCCP, Division of Pulmonary and Critical Care Medicine, Evanston Northwestern Healthcare, 2650 Ridge Ave, Evanston, IL 60201; e-mail: [email protected]

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was 19.8 ng/mL (normal range, 0.6 to 3.5 ng/mL), and troponin-I was 0.29 ng/mL (normal, ⬍ 0.06 ng/mL). Chest radiography revealed a normal heart size with mild pulmonary edema. CT of brain and chest showed no intracerebral hemorrhage, pulmonary embolism, or aortic dissection. An emergent, bedside echocardiogram did not show any regional wall-motion abnormalities. Serum chemistry findings were as follows: sodium, 140 mEq/L; potassium, 3 mEq/L; chloride, 102 mEq/L; HCO3-, 14 mEq/L; BUN, 27 mg/dL; creatinine, 1.6 mg/dL; and glucose, 481 mg/dL. CBC count was within normal limits. Urine drug survey findings were negative for illicit drugs, narcotic analgesics, and barbiturates. A venous blood gas analysis obtained from a central venous catheter revealed the following: pH 7.1; Pco2, 46 mm Hg; and Po2, 62 mm Hg. Carboxyhemoglobin and methemoglobin levels were 1.4% (normal range, 0 to 4%) and 0.6% (normal range, 0.4 to 1.5%), respectively. Lactic acid level was 6.3 mmol/L (normal range, 0.5 to 2.2 mmol/L). Hospital Course The patient was intubated and started on catecholamines for hemodynamic support in the ED. After stabilization in the ED, the patient was admitted to the coronary care unit (CCU) with the diagnosis of cardiopulmonary arrest due to myocardial infarction. After the patient’s BP improved, his skin was flushed and his lips were red. The patient was flaccid; unresponsive to pain, sound, and light; and had no discernible cranial nerve function. An arterial blood gas analysis obtained in the CCU while breathing 100% oxygen was bright red and showed pH 7.39 and Pao2 of 407 mm Hg. Despite improved hemodynamic parameters, repeat chemistry findings 8 h after hospital admission again revealed anion gap acidosis with a HCO3- of 16 mEq/L and a lactic acid level of 2.7 mmol/L. Shortly thereafter, the patient’s wife arrived at his bedside, where she commented that he looked unusually good given the circumstances. What is the diagnosis? CHEST / 122 / 3 / SEPTEMBER, 2002

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Table 2—Sources of Delayed Cyanide Toxicity

Diagnosis: Acute cyanide toxicity Cyanide inhibits intramitochondrial cytochrome oxidase by binding to both the protein and ferric ion portions of the cytochrome aa3 complex of the electron transport chain. By inhibiting electron transfer to molecular oxygen, cyanide prevents oxidative generation of adenosine triphosphate and reduction of nicotinimide adenine dinucleotide phosphate (NADP). Reduced availability of redox equivalents causes pyruvate to be used to make lactate by lactate dehydrogenase. This reaction regenerates redox equivalents by converting NADP in its reduced form to NADP. Cyanide is endogenously eliminated to the less toxic metabolite, thiocyanate, by hepatic rhodanase. Cyanide also causes lipid peroxidation in the CNS due to inhibition of antioxidant enzymes. The onset of symptoms depends on the amount, duration, and route of exposure (inhalational, oral, or skin) and ranges from a few minutes to days. Signs and symptoms of cyanide toxicity reflect cellular hypoxia and are often nonspecific. Thus, the diagnosis is usually based on a history of exposure in patients that present with rapidly developing coma, cardiovascular instability, and severe lactic acidosis in the setting of a high mixed venous oxygen saturation. Importantly, classic signs including bright red venous blood, profound metabolic acidosis, and bitter, almond breath are often absent (Table 1). The etiology of bitter, almond breath (or a musty odor) is the odor of limited amount of unmetabolized hydrogen cyanide excreted through breath. While both sodium and potassium cyanide are odorless, white solids, they can form hydrogen cyanide when exposed to atmospheric moisture or ingested on an empty stomach (acid environment). Cyanide-containing foods and compounds are frequently overlooked, delaying the diagnosis further (Table 2). Cyanide should be included in the differential diagnosis of rapid-onset coma, along with drug overdose and exposure to other toxins, such as hydrogen sulfide, carbon monoxide, and nicotine. Early CNS stimulation (dizziness, hyperventilation, headache, nausea, vomiting, feeling of suffocation,

Table 1—Most Common Findings of Cyanide Toxicity* Findings

Incidence (n ⫽ 21), %

Rapid loss of consciousness Metabolic acidosis GI irritation (postingestion) Rapid decrease in respiratory rate Hypotension

71 67 43 43 38

*Data are from Yen et al. 1074

Nitroprusside Acetonitrile (malononitrile, succinonitrile, allynitrile) Ioxynil (?)—a herbicide Plants containing amygdalin or cyanogenic glycoside (found in young leaves and seeds) Prunus species (almond, apricot, peach), Apple, Birdsfoot Trefoil, Braken Fern, Cassava (unprocessed), Sedges, Vetch, Sorphum whole plant (immature), Cotoneaster, Clover, Elderberry, Hydrangea, Jetberry bush, Lima beans (Puerto Rican), Lindseed, Pear Aliphatic thiocyanates Cyanogen and its halides (chemical warfare) Production of phencyclidine (potassium cyanide) Vitamin B17

confusion, restlessness, and anxiety) and tachypnea (due to hypoxic stimulation of carotid body) are followed by CNS and respiratory depression. Severe cyanide toxicity progresses to stupor, coma, opisthotonus, convulsions, fixed and dilated pupils, and death. Depression of the cardiovascular system usually requires higher doses of cyanide compared to those necessary for CNS depression. Tachycardia with hypertension is followed by bradycardia and hypotension (due to peripheral vasodilation). The ECG may display ischemic changes with erratic atrial and ventricular arrhythmias. Pulmonary edema may complicate severe intoxications. In severe poisoning, the skin is cold, clammy, and diaphoretic. Inhibition of oxygen utilization results in elevated venous oxygen levels that make cyanosis an unusual finding. Fundoscopic examination may be helpful, as retinal veins and arteries may appear equally red in color because of the elevated venous oxygen level. Central retinal edema can also occur. Elevated whole blood cyanide levels are necessary for definitive diagnosis. As cyanide is a volatile and unstable compound, blood should be collected according to specific instructions given by the reference laboratory that will perform the assay. Cyanide levels correlate with the severity of clinical picture but require 4 to 6 h to measure, and thus are only useful for confirmation of poisoning. A level of 0.5 to 1 mg/L (19.2 to 38.5 ␮mol/L) is associated with flushing, hypertension, and tachycardia; 1 to 2.5 mg/L (38.5 to 96.1 ␮mol/L) is associated with decreased CNS function and may be fatal; levels ⬎ 3 mg/L (115.4 ␮mol/L) are usually fatal. The serum half-life of cyanide is 2 h. A plasma lactate concentration ⬎ 8 mmol/L is 94% sensitive and 70% specific for a blood cyanide level ⬎ 1 mg/L (SI, 38.5 ␮mol/L). Although elevated serum cyanide levels are necessary for a definitive diagnosis, it is reasonable to Pulmonary and Critical Care Pearls

start empiric therapy with sodium thiosulfate in a setting consistent with cyanide exposure, such as severely acidotic house-fire victims. Initial supportive treatment includes aggressive cardiopulmonary support with fluids, catecholamines, antiarrhythmics (if necessary), and 100% oxygen. Health-care providers should not inhale the victim’s expired air nor perform mouth-to-mouth resuscitation, and gloves should be worn to prevent CNS exposure from the patient’s skin. Combination antidote strategies are designed to reverse binding of cyanide to cytochrome oxidase, induce methemoglobinemia, and convert cyanide to less toxic thiocyanate (which is excreted in the urine) [Table 3]. Oxygen increases the rate of conversion of reduced cytochrome oxidase to the oxidized form, allowing resumption of electron transport. Hyperbaric oxygen is a controversial adjunct. Sodium thiosulfate provides a sulfur molecule to rhodanase, which accelerates the conversion of cyanide to sodium thiocyanate. Concomitant administration of cobaltous chloride potentiates the effects of sodium thiosulfate. Due to adverse effects associated with cobalt (ie, hypotension, ventricular tachycardia, metabolic acidosis), cobalt ethylenediamine tetra-acetic acid (EDTA) should be reserved only for severe cyanide poisoning. Nitrites act by inducing the formation of methemoglobin, which has a stronger affinity for cyanide than cytochrome oxidase. The reaction between methemoglobin and cyanide forms cyanomethemo-

globin, which protects from further cyanide toxicity. Methemoglobin levels should be kept between 5% and 20% to prevent the adverse effects (ie, cyanosis). Paradimethylaminophenol (4-DMAP) has a mechanism of action similar to nitrites, does not cause hypotension, and induces methemoglobin formation faster than nitrites. Hydroxocobalamine works by binding to cyanide in exchange for a hydroxyl group to form cyanocobalamine, which is subsequently eliminated via the kidneys. Typically, approximately 4 g of hydroxocobalamine can bind 200 mg of cyanide. Neither 4-DMAP nor hydroxocobalamine are currently available in United States. Subsequently, during the first hospital day, the family informed us that an empty drinking glass, a bottle of potassium cyanide, and a suicide note had been found at the side of the bathtub. The patient was started on sodium thiosulfate to enhance cyanide elimination, which was associated with marked improvement of his acidosis and BP. Retrospective review of the patient’s presentation shows a high venous Po2 (62 mm Hg), access to cyanide (he was a biochemist who owned a small chemical company), facial flushing, bright-red blood, mydriasis, cardiovascular instability, and lactic acidosis, all of which are suggestive of cyanide toxicity. A whole-blood cyanide level measured 18 h after ingestion (approximately nine half-lives) was 1 mg/L. On the second hospital day, following correction of the acidosis and discontinuation of catecholamine support, the patient remained in coma with no corneal, pupillary, oculocephalic, or oculovestibular reflexes. Following a positive apnea test result, he was pronounced brain dead.

Table 3—Treatment of Cyanide Toxicity Cardiopulmonary resuscitation/support 100% O2 Gastric decontamination (for ingestions) Sodium thiosulfate (25% solution) Adults, 12.5 g IV over 10 min after sodium nitrite Pediatric patients, 1.1 to 1.95 mL/kg IV May repeat one half dose Induction of methemoglobinemia Amyl nitrite, pearls, 0.18 to 0.3 mL by inhalation, inhale for 30 s Sodium nitrite Adults, 300 mg IV Pediatric patients, 0.15–0.33 mL/kg IV up to 10 mL of 3% solution 4-DMAP Others Hydroxocobalamine, 4 g IV Cyanokit (Orphan Medical; Minnetonka, MN) Combined with 8 g of sodium thiosulfate Dicobalt EDTA, 300–600 mg IV Kelocyanor (SERB ⫽ L’Arguenon; Paris, France; not available in United States) Sodium bicarbonate, 1 to 2 mEq/kg IV to treat severe acidosis Hyperbaric O2 if no response to O2 therapy or for smoke inhalation

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Clinical Pearls 1. Cyanide inhibits mitochondrial cytochrome oxidase (cytochrome aa3) leading to anaerobic glycolysis and lactic acidemia. 2. Signs and symptoms of cyanide toxicity are nonspecific reflecting cellular hypoxia. Thus, the diagnosis is usually based on the history of exposure. 3. Classic signs including bright red venous blood, profound metabolic acidosis, and bitter, almond breath often are absent. 4. Elevated serum cyanide levels are necessary for definitive diagnosis but require 4 to 6 h to obtain; therefore, levels are useful only for confirmation of poisoning. 5. A plasma lactate level ⬎ 8 mmol/L should suggest the diagnosis. 6. Cyanide poisoning should be included in the differential diagnosis of acute-onset coma with cardiovascular instability. 7. Treatment strategies include reversal of binding of cyanide to cytochrome oxidase, induction of metCHEST / 122 / 3 / SEPTEMBER, 2002

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hemoglobin, and conversion of cyanide to the less toxic thiocyanate. Selected Reading Baud J, Borron SW, Megarbane B, et al. Lactic acidosis in cyanide poisoning: pathophysiology and clinical considerations [abstract]. J Toxicol Clin Toxicol 2001; 39:244 Eyer P. Therapeutic implication of the toxicokinetics and toxicodynamics in cyanide poisoning. J Toxicol Clin Toxicol 2000; 38:212–214

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Leikin JB, Paloucek FP. Poisoning and toxicology handbook. 3rd ed. Hudson, OH: Lexicomp Publishers, 2002; 424 – 426 Penney DG, Porter WE. Cyanide. In: Webb AR, Shapiro MJ, Singer M, et al, eds. Oxford textbook of critical care. New York, NY: Oxford University Press, 1999; 647– 649 Salkowski AA, Penney DG. Cyanide poisoning in animals and humans: a review. Vet Hum Toxicol 1994; 36:455– 466 Taitelman U. Acute cyanide poisoning. In: Hall JB, Schmidt GA, Wood LDH, eds. Principles of critical care. New York, NY: McGraw-Hill, 1992; 2125–2129 Yen D, Tsai J, Wang LM, et al. The clinical experience of acute cyanide poisoning. Am J Emerg Med 1995; 13:524 –528

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