乙二醇中毒

case records of the massachusetts general hospital T h e n e w e ng l a nd j o u r na l o f m e dic i n e n engl j med 354;10 www.nejm.org march 9, 2006 1065 Founded by Richard C. Cabot Nancy Lee Harris, m.d., Editor Sally H. Ebeling, Assistant Editor Jo-Anne O. Shepard, m.d., Associate Editor Christine C. Peters, Assistant Editor Case 7-2006: A 47-Year-Old Man with Altered Mental Status and Acute Renal Failure J. Kimo Takayesu, M.D., M.Sc., Hasan Bazari, M.D., and Michael Linshaw, M.D. From the Department of Surgery ( J.K.T.) and the Nephrology Division, Depart- ment of Medicine (H.B.), Massachusetts General Hospital; and the Department of Surgery (J.K.T.), the Nephrology Division, Department of Medicine (H.B.), and the Nephrology Division, Department of Pe- diatrics (M.L.), Harvard Medical School. N Engl J Med 2006;354:1065-72. Copyright © 2006 Massachusetts Medical Society. Pr esen tat ion of C a se A 47-year-old man was transferred to the emergency department of this hospital at 10 a.m. on a day in early June because of altered mental status and acute renal fail- ure. At approximately 8 p.m. the previous evening, the patient had been behaving normally at dinner with his family. After dinner, he went outside to work on his car. According to his wife, when he later returned to the house, his speech was slurred and he was lethargic. By 9 p.m., the patient was vomiting and becoming increas- ingly lethargic. He went to bed, and at 3:30 a.m., his wife found him unresponsive. She called emergency medical services, and the patient was taken to the emergency department of a local hospital. The patient had not had recent fevers, illnesses, or depressive symptoms. He had irritable bowel syndrome (for which he took atropine and diphenoxylate), chronic back pain, and anxiety. He was allergic to penicillin. There was no personal or fam- ily history of major medical problems. He had a 30 pack-year history of smoking and a history of alcohol abuse, but he had not consumed alcohol in the past year. His wife did not believe that he used illicit drugs. There were no empty pill bottles found in the house, and the patient did not have known access to other prescrip- tion medications. On arrival in the emergency department, the patient was somnolent and unable to follow commands; the blood pressure was 85/40 mm Hg, and the heart rate 75 beats per minute. His mental status worsened, and the trachea was intubated for airway protection with use of rapid-sequence induction with 20 mg of etomidate and 120 mg of succinylcholine. A chest radiograph showed an infiltrate in the left lower lobe that was consistent with pneumonia. A computed tomographic (CT) scan of the head revealed no abnormalities except for an air–fluid level in the left mas- toid air cells that was suggestive of mastoiditis. An orogastric tube was placed, and 50 g of activated charcoal was given; in addition, 900 mg of clindamycin and 500 mg of metronidazole were given intravenously for possible aspiration pneumonia. After endotracheal intubation, the arterial pH was 6.97, the partial pressure of oxygen 182 mm Hg, and the partial pressure of carbon dioxide 34 mm Hg; the level of carbon monoxide was undetectable. The creatinine level was 3.8 mg per deciliter (336 μmol per liter), and the white-cell count was 30,000 per cubic millimeter. A continuous intravenous infusion of sodium bicarbonate (150 mmol per liter) in a Downloaded from www.nejm.org on January 24, 2010 . Copyright © 2006 Massachusetts Medical Society. All rights reserved. T h e n e w e ng l a nd j o u r na l o f m e dic i n e n engl j med 354;10 www.nejm.org march 9, 20061066 solution of 5 percent dextrose in water was started at a rate of 250 ml per hour, and the patient was transferred to the emergency department of this hospital. On arrival at this hospital, the patient was in- tubated and sedated and unresponsive to painful stimuli. The patient’s blood pressure was 137/88 mm Hg, the heart rate 80 beats per minute, and the temperature 36.2°C; he was ventilated at a rate of 30 breaths per minute with an oxygen satura- tion of 99 percent and a fraction of inspired oxygen of 1.0. His pupils were equal, round, and reactive at 3 mm. The corneal reflex was present, and the vestibulo-ocular reflex was absent. An endotra- cheal tube was in place. The neck was supple without lymphadenopathy. Rhonchi were present bilaterally. Cardiac auscultation revealed no abnor- malities. The abdomen was soft, with active bowel sounds. A Foley catheter was draining clear urine. The rest of the examination was normal. The placement of the endotracheal tube was confirmed by bedside end-tidal carbon dioxide calorimetry. A central venous pressure line was placed in the right internal jugular vein, and in the process a transient run of ventricular tachycar- dia occurred, which terminated with retraction of the guidewire. A chest radiograph obtained with a portable device showed no pneumothorax and a small left perihilar opacity. The central venous pressure was 10 to 13 mm Hg. The white-cell count was 27,000 per cubic millimeter, with 95 percent neutrophils; the rest of the complete blood count was normal. The results of other labora- tory tests are shown in Table 1. After a review of the CT scan obtained at the first hospital, van- comycin (1 g) and ceftriaxone (2 g) were admin- istered intravenously for empirical treatment of possible meningitis. An electrocardiogram showed normal sinus rhythm without marked prolonga- tion of the QRS complex or the QT interval. Table 1. Results of Laboratory Tests.* Variable Normal Range Day 1 Day 2 Day 8 Day 20 1 hr, 4 min after Admission 1 hr, 9 min after Admission 5 hr, 48 min after Admission 12 hr, 35 min after Admission Sodium (mmol/liter) 135–145 147 149 153 140 137 136 142 Potassium (mmol/liter) 3.4–4.8 4.1 2.4 2.6 4.8 3.8 5.2 5.1 Chloride (mmol/liter) 100–108 110 107 100 103 108 Carbon dioxide (mmol/liter) 23–31.9 13.6 25.3 31.5 17.8 26.8 Urea nitrogen (mg/dl) 8–25 23 17 15 96 56 Creatinine (mg/dl) 0.6–1.5 2.8 2.7 2.6 12.6 3.6 Glucose (mg/dl) 70–110 208 141 99 163 130 115 90 Calcium (mg/dl) 8.5–10.5 7.6 8.8 8.0 8.6 9.1 Calcium, ionized (mmol/ liter) 1.14–1.30 0.74 0.55 1.22 Phosphorus (mg/dl) 2.6–4.5 4.3 2.8 1.1 7.0 5.7 Magnesium (mEq/liter) 1.4–2.0 1.5 1.3 1.3 2.1 1.6 Fraction of inspired oxygen (per liter) No normal value 0.7 0.5 Arterial pH 7.35–7.45 7.10 7.34 7.45 Arterial partial pressure of carbon dioxide (mm Hg) 35–42 33 28 36 Arterial partial pressure of oxygen (mm Hg) 80–100 139 234 105 Osmolality (mOsm/kg) 280–296 321 * To convert the values for urea nitrogen to millimoles per liter, multiply by 0.357. To convert the values for creatinine to micromoles per liter, multiply by 88.4. To convert the values for glucose to millimoles per liter, multiply by 0.5551. To convert the values for calcium to millimoles per liter, multiply by 0.250. To convert the values for phosphorus to millimoles per liter, multiply by 0.3229. To convert the values for mag- nesium to millimoles per liter, multiply by 0.500. Downloaded from www.nejm.org on January 24, 2010 . Copyright © 2006 Massachusetts Medical Society. All rights reserved. case records of the massachusetts gener al hospital n engl j med 354;10 www.nejm.org march 9, 2006 1067 Approximately 30 minutes after his arrival at this hospital, the patient had a generalized tonic– clonic seizure. Lorazepam was administered in- travenously every two minutes in doses of 2 mg up to a total of 20 mg. After 10 minutes of con- tinuous seizure activity, phenytoin (1 g) was ad- ministered intravenously at a rate of 50 mg per minute. Administration of phenobarbital was in preparation when the seizure activity ceased at 20 minutes. The results of laboratory tests are shown in Table 1. The anion gap was calculated at 25 mmol per liter. The measured serum osmolality was 321 mOsm per kilogram, and the patient’s initial osmolal gap was calculated at 8 mOsm per kilogram. Calcium gluconate (2 g), potassium chloride (1 liter of a 40-mmol solution in normal saline), and magnesium sulfate (2 g) were given. Toxicologic screening of serum was negative for ethanol, acetaminophen, and salicylates, and toxi- cologic screening of urine was also negative. Nu- merous needle-shaped crystals were seen in the urinary sediment. Fomepizole (1 g; 15 mg per kilogram of body weight) was administered intravenously, and the nephrology division was consulted for immediate hemodialysis. A double-lumen hemodialysis cath- eter was placed in the right femoral vein, and hemodialysis was initiated. Results of laboratory tests obtained five hours after admission are shown in Table 1. The patient was admitted to the medical intensive care unit for further care. Differ en ti a l Di agnosis Dr. J. Kimo Takayesu: I was involved in the case of this 47-year-old man, who had an acute onset of altered mental status, acute renal failure, and a severe metabolic acidosis associated with an an- ion gap. These findings initially gave rise to a broad differential diagnosis, which was quickly narrowed by the additional finding of typical crystals of calcium oxalate in a urine specimen. The Anion Gap The anion gap is the difference between the mea- sured concentrations of serum sodium and the total of the main serum anions chloride and bi- carbonate (anion gap = Na – Cl + HCO3); a normal anion gap is caused by the presence of negatively charged proteins that are not measured by serum analyzers, mainly albumin, and ranges from 3 to 11 mmol per liter.1,2 An elevated anion gap is caused by either an excess of unmeasured serum anions in addition to albumin or a paucity of un- measured cations such as calcium or magnesium. This patient had a profoundly elevated anion gap of 25 mmol per liter, which was not explained by the degree of hypocalcemia and hypomagnese- mia, and thus prompted a search for the presence of unmeasured serum anions. Causes and effects of anion-gap metabolic acidosis Anion-gap metabolic acidosis has four main causes: lactic acidosis, ketoacidosis, renal failure, and ingested toxins and their metabolites (Table 2). An anion gap of 25 mmol per liter correlates strongly with the presence of one of these condi- tions3 and is often due to multiple concurrent con- ditions. This patient’s acidosis was probably caused by a combination of lactic acidosis from periph- eral hypoperfusion and tissue hypoxia, acute re- nal failure, and an ingested toxin. The physiolog- ical effects of metabolic acidosis include a reflexive increase in respiratory drive, depressed cardiac contractility, peripheral arterial dilata- tion, increased susceptibility to cardiac arrhyth- mias, central venoconstriction, a predisposition to pulmonary edema, depression of the central nervous system, and glucose intolerance. This pa- Table 2. Four Main Causes of Anion-Gap Metabolic Acidosis. Lactate Carbon monoxide Cyanide Isoniazid (>30 mg/kg) Iron Salicylates (cytochrome poisoning) Metformin Acute alcohol intoxication Ketoacidosis Diabetic ketoacidosis Alcoholic ketoacidosis Renal failure Uremia, decreased secretion of ammonium, hydro- gen sulfate, hydrogen phosphate Toxins and metabolites Toluene Methanol, ethylene glycol, paraldehyde (metabolized to formate, oxalate, acetate) Downloaded from www.nejm.org on January 24, 2010 . Copyright © 2006 Massachusetts Medical Society. All rights reserved. T h e n e w e ng l a nd j o u r na l o f m e dic i n e n engl j med 354;10 www.nejm.org march 9, 20061068 tient was mechanically hyperventilated after in- tubation in an attempt to maximize respiratory compensation for his metabolic acidosis.4-6 His hyperglycemia was probably a result of the infu- sion of bicarbonate in 5 percent dextrose he was receiving at the time of transfer, as well as a stress response. The episode of ventricular tachy- cardia that was precipitated by the guidewire in- sertion during placement of the central venous line may have been a result of the acidosis and the electrolyte abnormalities. This patient’s obtundation and hypotension probably resulted in tissue hypoxia with lactate overproduction, causing lactic acidosis. The treat- ment for lactic acidosis relies on restoration of adequate tissue perfusion through intravenous volume repletion and supplemental oxygen, both of which this patient received. The use of vaso- pressors can also be beneficial if tissue hypoper- fusion persists after intravenous volume repletion, but these agents were not required in this case.7 A sodium bicarbonate infusion was begun; bi- carbonate infusions may help to improve cardiac function when the pH falls below 7.20.8,9 How- ever, the infusion can also cause fluid overload and paradoxical tissue acidosis in patients with limited respiratory reserve, cardiac failure, or ar- rest. When the patient arrived here, the pH had corrected to 7.10, and the central venous pressure and blood pressure were normal. Diabetic ketoacidosis often occurs in patients with insulin-dependent diabetes in whom an acute physiological stressor results in the accumulation of acetoacetate and β-hydroxybutyrate from fatty- acid metabolism. This patient had no history of insulin dependence, making this an unlikely cause of his acidosis. He did have a remote history of alcohol abuse, making alcoholic ketoacidosis a possible contributing diagnosis. An abrupt dis- continuance of alcohol consumption by a long- time alcohol user results in a starvation state that is worsened by subsequent vomiting and dehydra- tion. The ketosis in this condition is predomi- nantly from β-hydroxybutyrate, which is not de- tected by the nitroprusside ketone reaction used to detect acetoacetate. This patient received ap- propriate treatment for alcoholic ketoacidosis, including intravenous hydration with a dextrose solution and electrolyte replacement; however, given the acute onset of profound acidosis and the history of recent sobriety, other diagnoses had to be considered. An important feature of this case is the new onset of renal failure. Acidosis in renal failure is principally due to an accumulation of acids and a reduction of ammonium production due to de- creased nephron mass. Acute renal failure typi- cally presents with a combination of hyperchlo- remic acidosis and anion-gap metabolic acidosis. Bicarbonate levels usually remain greater than 15 mmol per liter, and the anion gap usually does not exceed 20 mmol per liter. This patient had a large anion gap, severe acidemia with a relatively low creatinine level, and no history of previous renal disease. Thus, although renal failure probably con- tributed to this patient’s severe acidosis, it was unlikely to be the primary cause. Many toxins and drugs can induce acidosis. Carbon monoxide poisoning causing lactic acido- sis was ruled out by the other hospital. Salicylates increase lactate production by poisoning mito- chondrial cytochromes. However, in this patient toxicologic screening did not show the presence of salicylates. Toxic alcohols, such as methanol and ethylene glycol, would be a primary consid- eration in this case of anion-gap acidosis. They are converted by alcohol dehydrogenase to toxic anionic acids that increase the anion gap. In ad- dition, these alcohols are osmotically active in their native forms before they are metabolized, and they cause an increase in the measured se- rum osmolality. This osmolal increase is esti- mated by the difference between the measured osmolality and the calculated osmolality, deter- mined as follows: (2 × the serum sodium level) + (the blood urea nitrogen level ÷ 2.8) + (the blood glucose level ÷ 18) — known as an osmolal gap. When the osmolal gap exceeds 10 mmol per li- ter, the presence of a toxic alcohol must be con- sidered. This patient had an osmolal gap of only 8 mmol per liter, which could argue against the presence of a toxic alcohol. However, by the time he came to medical attention, it is probable that most of the osmotically active alcohol would have already been converted to an anionic metabolite, which would not contribute to the serum osmo- lality. The needle-shaped crystals found in the urine on his arrival in the emergency department of this hospital are characteristic of calcium oxa- late, a metabolite of ethylene glycol; this finding, together with the presence of anion-gap acido- sis, altered mental status, and acute renal tubu- lar injury, strongly supports the diagnosis of eth- ylene glycol intoxication. Downloaded from www.nejm.org on January 24, 2010 . Copyright © 2006 Massachusetts Medical Society. All rights reserved. case records of the massachusetts gener al hospital n engl j med 354;10 www.nejm.org march 9, 2006 1069 DR . J. K IMO TA K A Y ESU’S DI AGNOSIS Ethylene glycol intoxication. Pathol o gic a l Discussion Dr. Michael Linshaw: The original sample of urinary sediment from this patient was not available to photograph. However, the morphologic structure of urinary crystals can be helpful in establishing a diagnosis. Calcium oxalate crystals are of two types (Fig. 1): calcium oxalate dihydrate crystals, which are typically octahedrons, and calcium oxa- late monohydrate crystals, which are needle-shaped. Calcium oxalate monohydrate crystals are not of- ten seen in urinary sediment, but they are typical, and therefore very suggestive, of ethylene glycol ingestion. Calcium oxalate dihydrate crystals may be seen in other conditions and are therefore less specific for the diagnosis. If calcium oxalate crys- tals are seen within a cast or are associated with dysmorphic red cells (defined as those showing marked variation in size and shape), this finding suggests the possibility of crystal nephropathy. Discussion of M a nagemen t Dr. Hasan Bazari: This man presented with the triad of depression of the central nervous system with seizures, acute renal failure, and anion-gap met- abolic acidosis. An evaluation in the emergency department led to the diagnosis of ethylene gly- col intoxication, and the nephrology division was consulted regarding management. The two alcohols that typically cause both a severe anion-gap metabolic acidosis and an os- molal gap are methanol and ethylene glycol.10 The osmolal gap is a useful way to detect the pres- ence of alcohols, but it has several pitfalls. The serum osmolality can be measured by determin- ing either the freezing-point depression or the boiling-point elevation (the vapor-pressure meth- od). The latter is unreliable in the presence of volatile substances such as ethanol and metha- nol,11 but not with ethylene glycol because it has a high boiling point.12 Once the osmolal gap is calculated, if the ethanol concentration is known, the presence of a second unmeasured osmole can be deduced. However, ethylene glycol, with a rela- tively high molecular weight of 62, contributes fewer osmoles at a given serum concentration than alcohols of lower molecular weight. Hence, at a concentration of 21 mg per deciliter, the contri- bution of ethylene glycol to the osmolality may be only 4 mOsm per kilogram and at a lethal dose of 50 mg per deciliter, the contribution to osmo- lality may be only 8 mOsm per kilogram. Exces- sive reliance on the osmolal gap can lead one to omit consideration of ethylene glycol intoxication if the gap is below that considered to be normal, as happened in this case. Finally, the time that has elapsed since the ingestion is also important. Alcohols that are metabolized, such as ethylene glycol, will contribute less to the osmolal gap and more to the anion gap as they are metabolized, which is what probably occurred in this patient.