Unresponsive Patient Admitted to the Emergency Department

case study [chemistry]

Past Medical History Significant for recent admission to the same hospital for seizures secondary to cocaine overdose.

Unresponsive Patient Admitted to the Emergency Department Irfan Warraich, MD,1 Ashwani Kumar, MD,2 Ratna Grewal, MD,1 Rodney Tucay, MD,1 Jeffrey W. Oliver, MD,1 Dale M. Dunn, MD,1 Charles A. Bradley, PhD1 1Departments of Pathology and 2Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX DOI: 10.1309/TERLDXMF2F3LHRDR

Patient 30-year-old woman. Chief Complaint She was brought to a hospital Emergency Department (ED) after being found at home by her children who were unable to arouse her. Empty bottles of Carisoprodol (2-methyl-2propyl-1,3-propanediol carbamate isopropylcarbamate) and Toradol (Ketorolac Tromethamine) were found near the patient. A bottle containing Paxil (paroxetine hydrochloride) was also found with 2 pills missing from it.

Physical Examination Upon arrival at the ED, she was unresponsive to verbal and deep painful stimuli and was intubated. There was no history of observed seizure activity, fever, or bladder or bowel incontinence. Her vital signs were unremarkable, except for tachycardia with a normal S1, S2, and no murmurs. Pupils were dilated and fixed. She had no papilledema or gag reflex. Her chest was clear to auscultation bilaterally. Neurologic examination revealed a significantly diminished mental status. The patient was unresponsive to pain and exhibited decerebrate posturing with sternal rub. Deep tendon reflexes were exaggerated throughout and had sustained ankle clonus. Mechanical ventilation was initiated, and she was breathing spontaneously above the ventilator rate. She exhibited no withdrawal to pain in all 4 extremities. Electrocardiogram revealed only sinus tachycardia and no widening of QRS complexes. A CT scan of the head was normal. She was admitted to the medical intensive care unit for supportive treatment. Principal Laboratory Results [T1].

T1

Principal Laboratory Findings Hours After Presentation Test

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Chemistry Sodium Potassium Chloride CO2 BUN Creatinine Alkaline phosphatase AST ALT Total bilirubin Direct bilirubin CK Coagulation Platelet count PT PTT Fibrinogen Qualitative drug screen - serum Ethanol Salicylates Quantitative drug screen - serum Acetaminophen Phenytoin Qualitative drug screen – urine TCAs

0

24

>24

“Normal” Reference Interval

141 4.5 107 16 33 1.2 138 2,101 4,766 7.4 5.8 8352

136 4.0 107 14 50 2.3 120 116 3,253 6.1 5.2

140 2.3 112 17 46 2.3 120 280 1,434 5.9 4.6

137-145 mmol/L 3.6-5.0 mmol/L 99-110 mmol/L 22-30 mmol/L 7-17 mg/dL 0.7-1.2 mg/dL 38-126 IU/L 14-36 IU/L 9-52 IU/L 0.2-1.3 mg/dL 0.0-0.3 mg/dL 30-135 U/L

236 35.6 34.7 110

114 41.1 67

79 35.1 70.5 115

140-400 x 103/µL 10.5-13.1 sec 23.1-33.8 sec 200-400 mg/dL

Neg Neg

Neg Neg

35

10-30 mg/mL 10-20 mg/mL

22.2 Pos

Neg

BUN, blood urea nitrogen; AST, aspartate aminotransferase; ALT, alanine aminotransferase; CK, creatine kinase; PT, prothrombin time; PTT, partial thromboplastin time; TCAs, tricyclic antidepressants; Pos, positive; Neg, negative

laboratorymedicine> october 2003> number 10> volume 34

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Questions: 1. What is(are) this patient’s most striking laboratory result(s)? 2. How do you explain this patient’s most striking laboratory result(s)? 3. What is this patient’s most likely diagnosis(es)? 4. What are the usual causes of and outcomes associated with this patient’s condition? 5. How should this patient’s condition be treated? Possible Answers: 1. Recent history of seizures secondary to cocaine abuse and ED/hospital admission findings of unresponsiveness to verbal and deep pain stimuli with dilated and fixed pupils and no gag reflex; decreased CO2; increased BUN, creatinine, and alkaline phosphatase (admission sample only) concentrations; markedly increased AST, ALT, total and direct bilirubin, and CK concentrations; multiple abnormal coagulation tests with results worsening over time; modestly increased serum acetaminophen and phenytoin concentrations; and a positive urine drug screen for TCAs [T1]. 2. These clinical and laboratory findings were suspicious for postictal phase or non-convulsive status epilepticus or drug toxicity due to overdose of either acetaminophen or a TCA (positive urine drug screen for TCAs). However, TCA overdoses are characterized typically by the triad of signs and symptoms associated with coma, convulsions, and cardiac conduction abnormalities [ie, QRS complex widening, bundle branch block, and atrioventricular (A-V) block]. Our patient had no evidence of convulsions and cardiac conduction abnormalities, suggesting that the positive urine drug screen for TCAs was either a false positive or reflected non-toxic levels of TCAs. On the other hand, acute liver failure (eg, elevated AST, ALT, and bilirubin concentrations), coagulation defects (eg, increased PT and PTT, decreased fibrinogen concentration, and thrombocytopenia), cardiomyopathy (eg, increased total CK), and renal failure (eg, increased BUN and creatinine concentrations) are characteristic findings in phases II (24 to 48 hours post-ingestion) or III (3 to 5 days post-ingestion) of acetaminophen overdose [T2]. 3. Most likely diagnosis: acute liver failure secondary to acetaminophen overdose.

Acetaminophen, or N-acetyl-p-aminophenol (APAP), is one of the most frequently used medications in the United States. Its use alone or in combination preparations is widespread because of its analgesic and antipyretic properties and presumed safety in recommended doses. However, APAP is responsible for more drug overdose hospitalizations than any other common medication.1 Acetaminophen is metabolized by hepatocytes. It is usually eliminated as a glucuronide or sulfate conjugate. Following overdose, however, the conjugation pathways become saturated, leading to accumulation of reactive intermediates such as N-acetyl-benzoquinoneimine, mercapturic acid, and probably others.2 These reactions involve the cytochrome oxidase P-450 system, and the metabolites are normally detoxified by endogenous glutathione. When glutathione stores are depleted, hepatocyte necrosis ensues, typically with a centrilobular distribution. Liver necrosis can result from an acute overdose of a large amount of APAP, or from accumulation over several days. 4. In a study of 94 fatal acetaminophen overdose cases with known reasons for exposure, most were associated with suicidal intentions.3 However, in 25% of these cases, unintentional therapeutic error and intentional misuse without suicidal intent were the reasons for the overdose. Although the intentions of our patient were not clear, suicidal intent appeared unlikely. Unintentional overdose due to the presumed safety of acetaminophen appeared to be the likely cause. Outcomes in cases of acetaminophen overdose are dependent upon several factors, including the amount of drug ingested and the time period between ingestion and initiation of drug-specific therapy. In cases of delayed treatment, death from irreversible liver failure due to the hepatotoxic effects of reactive acetaminophen intermediates may occur. Thrombocytopenia, as observed in our patient, is a well-reported clinical feature of acetaminophen toxicity and strongly correlates with the degree of hepatotoxicity, although it does not correlate with serum acetaminophen levels.4 Thus, the finding of thrombocytopenia early in the course of acetaminophen toxicity may help in identifying patients prone to severe hepatotoxicity. Acute renal failure, as observed in our patient, occurs in less than 2% of all acetaminophen poisonings and 10% of severely poisoned patients.5 Acute tubular necrosis occurring with acetaminophen toxicity has been described previously.5,6

Clinical Stages of Acetaminophen Toxicity*

T2

Stage

Time Post-Ingestion

Clinical and/or Laboratory Characteristics

I II

0.5 to 24 hours 24 to 48 hours

III

72 to 96 hours

IV

4 days to 2 weeks

Anorexia, nausea, vomiting, malaise, pallor, diaphoresis Resolution of the above characteristics; right upper quadrant abdominal pain and tenderness; elevated bilirubin, prothrombin time, INR, hepatic transaminases, oliguria Anorexia, nausea, vomiting, malaise may reappear; values for liver function tests peak; FHF with metabolic acidosis, INR >6, and renal dysfunction Resolution of hepatic dysfunction in survivors; oliguric renal failure; death from FHF

*Modified from Linden CH, Rumack BH: Acetaminophen overdose. Emerg Med Clin North Am. 1984;2:103. INR, International Normalized Ratio; FHF, fulminant hepatic failure

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5. With N-acetylcysteine (Mucomyst) to stimulate regeneration of glutathione. Early recognition of APAP toxicity is critical since outcomes are improved when antidotal treatment with Nacetylcysteine is started within 8 hours of the overdose. This can be difficult without a clinical history of APAP ingestion. Only nonspecific symptoms of abdominal pain, nausea, and vomiting generally appear within the first 24 hours postingestion. Symptoms often subsequently improve, but liver function tests foretell the acute hepatic failure that typically ensues by about the third day. Serum acetaminophen levels are extremely helpful in the diagnosis, but must be carefully related to the time since ingestion. A seemingly low level may still be a predictor of toxicity if the time since ingestion is long. The Rumack-Matthew nomogram [F1] plots this relationship and can be used to assess the need for N-acetylcysteine treatment.7 However, treatment with N-acetylcysteine is relatively harmless and should probably be initiated as soon as possible whenever APAP toxicity is suspected. Moreover, the therapeutic window of APAP is narrowed by various associated conditions. These conditions include inherited variations in hepatic enzyme activity, malnutrition,8,9 ethanol ingestion,10,11 drug

500

Probably hepatic toxicity

200 150

Possible hepatic toxicity

Acetaminophen (µg/ml plasma)

100

50

10 Hepatic toxicity unlikely

25%

5

726

1 4

8

12

16

20

24

Time (hr) after ingestion [F1] Rumack-Matthew nomogram for evaluating the probability of hepatotoxicity as a function of time and concentration postingestion of acetaminophen (From Rumack BH, Matthew H. Pediatrics. 1975;55:871. In: Rosen P, ed. Emergency medicine, 4th ed. St Louis: Mosby, 1998).

interactions, or concomitant medical disorders.12-18 Of these factors, nutritional factors and drug interactions are more likely to lead to toxicity at conventional doses of acetaminophen. Conditions associated with increased activity of P450-dependent pathways such as fasting,10 protein-calorie malnutrition,8,9 poorly controlled diabetes,17 and obesity,18 have been described. Chronic protein-calorie malnutrition, may also lead to low glutathione levels resulting in reduced detoxification.9 In addition, various drugs that may alter acetaminophen elimination or that stimulate the P-450 microsomal oxidase enzymes include Isoniazid, anticonvulsants (eg, phenobarbital, Phenytoin), rifampin, and ethanol.10-16 Severe toxicity has been reported in patients using these drugs concomitantly with APAP, even at low APAP levels.19 Our patient was treated with Phenytoin for her suspected seizure activity; this might have contributed to her morbidity and mortality. In addition, our patient was also taking carisoprodol, which has affected hepatic enzyme activities in rats,20 and could have interfered with her acetaminophen metabolism. We could not identify other more definite factors contributing to her hepatotoxicity. Patient’s Treatment and Course The patient was treated with phenytoin and N-acetylcysteine. N-acetylcysteine treatment was started approximately 8 hours after the patient presented to the hospital. On the following day, the patient’s overall condition deteriorated and she required vasopressor treatment. The neurological examination at that time revealed fixed and dilated pupils, no spontaneous breathing, no spontaneous ocular activity, and a negative cold caloric test. Electroencephalogram revealed a flat tracing suggestive of absent brain activity. These findings suggested brain death. After discussion with the patient’s family, ventilatory support was withdrawn and the patient was pronounced dead. Autopsy findings revealed a light yellow-brown homogeneous and congested hepatic parenchyma. The microscopic examination showed extensive microvesicular fatty change with centrilobular congestion and centrilobular necrosis of the hepatocytes. The brain examination revealed moderate global edema of the cerebral hemispheres. No other significant findings were identified. Results of the post mortem toxicology examination are shown in [T3]. In addition, quantitative assay of post-mortem blood samples for alcohols, including ethanol, isopropanol, methanol, and n-propanol, were negative. A qualitative TCA screen and a spot test for salicylates were also negative. The fatal outcome in this case demonstrates that physicians should have high index of suspicion and consider acetaminophen toxicity in any patient who has ingested acetaminophen and has signs of acute hepatic dysfunction, even if acetaminophen levels are not markedly elevated. Moreover, clinicians should avoid focusing too much on a drug(s) associated with a previous history of illicit drug use and remember to correlate the serum acetaminophen level with the time post-ingestion. Keywords: acetaminophen, acute liver failure, N-acetylcysteine, Rumack-Matthew nomogram


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T3

Post-Mortem Blood Drug Findings Drug

Concentration, mg/mL

Acetaminophen Phenytoin Valproic acid Paroxetine Meprobamate Carisoprodol

63 nd 5.1 nd nd 2.7

9. Sauerwein RW, Mulder JA, Mulder L, et al. Inflammatory mediators in children with protein-energy malnutrition. Am J Clin Nutr. 1997;65:1534-1539. 10. Whitcomb DC, Block GD. Association of acetaminophen hepatotoxicity with fasting and ethanol use. JAMA. 1994;272:1845-1850. 11. Kaysen GA, Pond SM, Roper MH, et al. Combined hepatic and renal injury in alcoholics during therapeutic use of acetaminophen. Arch Intern Med. 1985;145:2019-2023. 12. Bray GP, Harrison PM, O’Grady JG, et al., Long-term anticonvulsant therapy worsens outcome in paracetamol-induced fulminant hepatic failure. Hum Exp Toxicol. 1992;11:265–270. 13. Nolan CM, Sandblom RE, Thummel KE, et al., Hepatotoxicity associated with acetaminophen usage in patients receiving multiple drug therapy for tuberculosis. Chest. 1994;105:408–411.

nd, none detectable

1. MJ Smilkstein. Acetaminophen. In: L.R. Goldfrank, ed, Toxicologic Emergencies, 6th ed. Stamford, CT: Appleton and Lange. 1998:541–542.

14. Minton NA, Henry JA, Frankel RJ. Fatal paracetamol poisoning in an epileptic. Hum Toxicol. 1998;7:33–34.

2. Corcoran GB, Mitchell JR, Vaishnar YN, et al. Evidence that acetaminophen and N-hydroxyacetaminophen form a common arylating intermediate, N-acetyp-benzoquinoneimine. Mol Pharmacol. 1980;18:1557-1562.

15. Chien JY, Peter RM, Nolan CM, et al. Influence of polymorphic Nacetyltransferase phenotype on the inhibition and induction of acetaminophen bioactivation with long-term isoniazid. Clin Pharmacol Ther. 1997;61:24-34.

3. Litovitz TL, Klein-Schwartz W, Dyher KS, et al. 1997 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med. 1998;16:443-497.

16. Forrest JA, Roscoe P, Prescott LF, et al. Abnormal drug metabolism after barbiturate and paracetamol overdose. BMJ. 1974;4:499-502.

4. Fischereder M. Thrombocytopenia following acute acetaminophen overdose. Am J Hematol. 1994;453:258-259. 5. Prescott LF. Paracetamol overdosage: Pharmacological considerations and clinical management. Drugs. 1983;25:290-314. 6. Curry RW, Robinson JD, Sughrue MJ. Acute renal failure after acetaminophen ingestion. JAMA. 1982;247:1012-1014. 7. Rumack BH, Matthew H. Acetaminophen poisoning and toxicity. Pediatrics. 1975;55:871-876. 8. Zhang W, Parentau H, Greenly RL, et al. Effect of protein-calorie malnutrition on cytochromes P450 and glutathione S-transferase. Eur J Drug Metab Pharmacokinet. 1999;24:141-147.

17. Song BJ, Veech RL, Saenger P. Cytochrome P450IIE1 is elevated in lymphocytes from poorly controlled insulin-dependent diabetics. J Clin Endocrinol Metab. 1990;71:1036-1040. 18. O’Shea D, Davis SN, Kim RB, et al. Effect of fasting and obesity in humans on the 6-hydroxylation of chlorzoxazone: a putative probe of CYP2E1 activity. Clin Pharmacol Ther. 1994;56:359-367. 19. Kearns GL, Leeder JS, Wasserman GS. Acetaminophen overdose with therapeutic intent. J Pediatr. 1998;132:5-8. 20. Mansour MM, Fathi MM. Effect of chronic administration of meprobamate on different enzymatic activities in liver and serum in rats. J Drug Res. 1989;18:189–200.

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