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Value of rapid screening for acetaminophen in all patients with intentional drug overdose
ORIGINAL CONTRIBUTION acetaminophen, overdose
Value of Rapid Screening for Acetaminophen in All Patients With Intentional Drug Overdose We performed a prospective study to determine the incidence of missed, potentially toxic acetaminophen poisoning in all patients with any type of intentional drug ingestion presenting to two large, county hospital emergency departments. Of 486 patients with drug ingestion seen during a fivem o n t h period, 114 (23.5%) were s u s p e c t e d of h a v i n g i n g e s t e d acetaminophen. Of these, 71 (62.3%) had insignificant acetaminophen levels (false-positive history). Of the 365 patients who were not suspected of having acetaminophen ingestion, seven patients (/.9%) were found to have elevated levels on rapid screening (false-negative history). Of these, only one patient had a potentially hepatotoxic level. We conclude that the incidence of missed, potentially serious acetaminophen overdose is very low in our study population. [Ashbourne JF, Olson KR, Khayam-Bashi H: Value of rapid screening for acetaminophen in all patients with intentional drug overdose. Ann Emerg Med October 1989;18:1035-1038.] INTRODUCTION Acetaminophen toxicity was first recognized in Great Britain in 1966 when Davidson and Eastham ~ described the acute hepatic and renal tubular necrosis associated with paracetamol (acetaminophen) overdose. Since the introduction of acetaminophen into widespread use in the United States, it has become one of the drugs most frequently ingested in cases reported to poison control centers. ~ Fortunately, an effective antidote (N-acetylcysteine, NAC) was discovered and is widely used in the management of acetaminophen overdose.3, 4 However, for NAC to be effective, it must be given within 12 to 16 hours after ingestion, s Acetaminophen intoxication has no recognizable specific clinical manifestations early in its course. Therefore, early diagnosis is based solely on the history and the serum acetaminophen concentration. 6 Because the history of ingestion is often unreliable or unavailable, Z,s there may be a delay in obtaining the serum acetaminophen concentration and a delay in recognition and treatment of the overdose; this may result in unnecessary morbidity or m o r t a l i t y . Thus, m a n y c l i n i c i a n s r o u t i n e l y order s e r u m acetaminophen determinations in all patients with intentional drug overdose, regardless of the history. However, no systematic study has been performed to evaluate this common practice. We performed a prospective study to determine the incidence of missed, potentially toxic acetaminophen poisoning in all patients with any type of intentional drug ingestion presenting to two large, urban county hospital emergency departments.
John F Ashbourne, MD, FACEP*t Kent R Olson, MD, FACEP*t Hassan Khayam-Bashi, MD~ Oakland, California San Francisco, California From the Department of Emergency Medicine, Highland General Hospital, Oakland, California;* the San Francisco Bay Area Regional Poison Control Center, San Francisco General Hospital;t and the Department of Laboratory Medicine, San Francisco General Hospital and the University of California, San Francisco. 4Received for publication March 2, 1988. Revisions received September 29, 1988, and May 30, 1989. Accepted for publication June 7, 1989. Partial funding (reagents) provided by Abbott Laboratories, Chicago, Illinois. Presented at the Annual Scientific Meetings of the American Association of Poison Centers/American Academy of Clinical Toxicology, Santa Fe, New Mexico, August 1986. Address for reprints: John F Ashbourne, MD, FACER Poison Control Centre, Foothills Hospital, 1403 29th Street NW, Calgary, Alberta, Canada T2N 2T9.
METHODS All patients 16 years and older who presented to the ED of Highland General Hospital or San Francisco General Hospital between February 1 and July 7, 1986, with any suspected or confirmed intentional drug ingestion were eligible for the study. Those with simple substance abuse (eg, nonsuicidal abuse of ethanol, cocaine, heroin) were excluded. Both hospitals are active university-affiliated teaching facilities with a combined annual ED census of more than 140,000. The study protocol received approval from the Committee on Human Research of the University of California, San Francisco, and the Human Subjects Protection Committee of
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ACETAMINOPHEN SCREENING Ashbourne, Olson & Khayam-Bashi
A l a m e d a County. All subjects received usual emergency care appropriate to their overdoses. As each patient was identified, a screening acetaminophen level was ordered immediately. Before receiving a report of the serum level, the patient's primary physician (attending or housestaff) was required to complete a brief questionnaire indicating whether acetaminophen ingestion was s u s p e c t e d and, if so, on what basis (Figure). Multiple choices were permitted. The physician was provided a choice on the questionnaire (selection E) that would indicate that he would routinely order acetaminophen screening regardless of the history. If this was the only choice selected on the questionnaire, this was considered a negative history. T h e p h y s i c i a n was told in advance the purpose of the study, m a x i m i z i n g the likelihood that a thorough history regarding acetaminophen ingestion would be obtained from the patient. When a patient with acetaminophen ingestion was identified through screening, routine care for acetaminophen overdose (including four-hour postingestion levels and NAC t r e a t m e n t , if indicated) was provided. Potentially hepatotoxic ser u m levels were identified by plotting the s e r u m level versus t i m e since i n g e s t i o n on the R u m a c k Matthew nomogram, s Serum acetaminophen determinations were performed on a stat basis at each facility using the TDx Therapeutic Drug Monitoring System (Abbott Laboratories, Chicago, Illinois). This system uses a fluorescence pol a r i z a t i o n i m m u n o a s s a y t h a t has minimal interference and a high degree of correlation with standard assays, i n c l u d i n g h i g h - p e r f o r m a n c e liquid chromatography. 9 In addition, it is inexpensive, fully automated, and can be performed in 15 minutes or less by a technician familiar with the procedure. (Test reagents were provided free of charge by Abbott Laboratories.) The limit of detection for this assay is 0.7 to 1.0 mg/L. To exclude t h e r a p e u t i c use or trivial overdose of acetaminophen we considered a serum level of less than 10 mg/L drawn within eight hours after ingestion to be clinically insignificant. C o m p l i a n c e w i t h the study was monitored at Highland Hospital on a 28/1036
FIGURE.
Study questionnaire.
daily basis by reviewing all ED charts from the previous day. Monitoring was accomplished at San Francisco General Hospital by reviewing Drug Abuse Warning N e t w o r k (DAWN) s u m m a r i e s of all drug-related ED visits and chart review of each overdose case. At San Francisco General Hospital, DAWN summaries are prepared daily by experienced poison center staff and are considered reliable screening for drug-related ED visits. Standard formulae were used for calculation of sensitivity, specificity, and positive and negative predictive values. ~o,11 RESULTS
During the five-month study period, 486 patients were included in the study - 211 from Highland General Hospital and 275 from San Francisco General Hospital (Table). Of these, 476 were identified prospectively, and ten were discovered later on retrospective chart review. During the same period, 101 eligible patients with drug ingestion were seen in the two EDs but were not included in the study, giving an overall compliance of 486 of 587 (83%). These 101 patients were eligible for the study but were o v e r l o o k e d for e n t r y by the treating physicians. They were not purposely excluded from the study. On review of their hospital charts, we could not find any patient in this group who had a missed acetaminophen overdose based on toxicological screen, hospital clinical course, or subsequent ED Visits. There were 365 patients (75.1%) with no suspected acetaminophen' ingestion who were found to have insignificant s e r u m a c e t a m i n o p h e n concentrations (less than 10 rag/L); these patients were defined as having a true-negative history. Forty-three p a t i e n t s (8.8%) were suspected of having ingested acetaminophen and were found to have elevated (more than 10 mg/L) serum acetaminophen levels; these patients were considered to have a true-positive history. Seventy-one patients (14.6%) had a h i s t o r y of acetaminophen ingestion but were found to have insignificant (less than 10 rag/L) acetaminophen levels; these were described as having a false-positive history. Finally, Annals of Emergency Medicine
Do you suspect acetaminophen ingestion in this patient? If yes, indicate why (more than one choice permitted): A B C D E
History from patient History from witness Pill bottles Clinical syndrome Standard screening test you use in your emergency practice
seven patients (1.4%) had no history or suspicion of acetaminophen ingestion but had elevated serum acetaminophen levels; these were considered false-negative histories. The sensitivity, specificity, and positive and negative predictive values of the history as a predictor of acetaminophen ingestion are shown (Table). Of the seven cases in which the history was falsely negative, only one p a t i e n t - a 41-year-old H i s p a n i c woman who presented with a history of diazepam ingestion - had what could be considered a p o t e n t i a l l y hepatotoxic level. Although she had also ingested acetaminophen (Tylenol ® and Excedrin PM®), this history was not initially obtained because she spoke no English. Her acetaminophen intoxication was discovered only after her screening level was reported as 196 mg/L (obtained 11 to 12 hours after ingestion). She was treated with NAC and recovered without complications. The other six patients with falsenegative history for acetaminophen ingestion had serum levels ranging from 14 to 104 rag/L; none were in the toxic range when plotted against time since ingestion on the standard c o n c e n t r a t i o n - t i m e n o m o g r a m . In none of these six cases was there an apparent reason for the false-negative history (ie, language barrier, confusion, or coma). All six patients were treated appropriately, and none developed hepatotoxicity. In 139 of the 486 patients (29%), the physician completing the questionnaire selected only E, indicating that despite a negative history, the physician would routinely screen for a c e t a m i n o p h e n . In all but one of these, the acetaminophen screen was negative (false-negative rate, 0.7%). 18:10 October 1989
TABLE. Results Highland General Hospital (%) True-negatives True-positives False-positives False-negatives Total cases Sensitivity of the history Specificity of the history Positive predictive value Negative predictive value
167 (79) 16 (8.6) 26 (12.3) 2 (1.0) 211 = .86 = .84 = .38 = .99
(Because the n u m b e r of physicians completing the questionnaires was very large and the participating physicians comprised a varied group of rotating residents and attending physicians, it was not possible to make any conclusions about the characteristics of the group choosing E on the questionnaire.) Laboratory turnaround times were available for 139 of the p a t i e n t s (66%) at Highland General Hospital. The average time to complete the assay from receipt of the specimen was 46 minutes. The most significant delay in performing the test was in obtaining the sample and transporting it to the laboratory. DISCUSSION Acetaminophen is a commonly ingested drug found in a variety of prescription and over-the-counter products. As our study indicates, an urban ED may expect that as many as 25% of its overdose p a t i e n t s will have i n g e s t e d a c e t a m i n o p h e n or claim to have done so. To screen these patients, it is essential that a reliable, rapid, quantitative test for a c e t a m i n o p h e n be available for a busy ED. The question is, should all drug-overdose p a t i e n t s r o u t i n e l y have a rapid a c e t a m i n o p h e n determination, regardless of the history of ingestion? The history of drug ingestion is frequently unreliable, 12-14 and determination of ingested drugs on purely clinical grounds may B~ difficult, especially in the case of acetaminophen. 6 Previous case reports have demonstrated that because of unreliable or u n a v a i l a b l e history, aceta m i n o p h e n i n g e s t i o n m a y be 18:10 October 1989
San Francisco General Hospital (%) 198 27 45 5 275
(72) (9.8) (16.4) (1.8)
Total (%) 365 43 71 7 486
(75) (8.8) (14.6) (1.4) (100)
missed, Z,8 and serious toxicity m a y e n s u e b e c a u s e t r e a t m e n t is delayed.S, 15 Because early recognition of a c e t a m i n o p h e n i n t o x i c a t i o n is necessary for proper antidotal treatment, m a n y physicians and poison centers now frequently recommend routine rapid acetaminophen levels in all patients with intentional drug overdose, regardless of history. 16,17 However, until now, this approach has never been subjected to serious study. We have d e m o n s t r a t e d that approximately one in 70 patients who presents with intentional drug ingestion to an urban general hospital ED will have unrecognized acetaminophen overdose, and approximately one in 500 will have potentially hepatotoxic levels. This finding is consistent with an earlier study of unselected drug overdoses is in which the only death in 592 consecutive cases was an unrecognized acetaminophen ingestion. These ratios m a y not apply to all ED patient populations. In other ED populations, patients m a y be m o r e reliable historians or may have a lower likelihood of a language barrier as a cause of an inaccurate history. Further studies m a y establish selective criteria for acetaminophen screening; however, a review of our seven patients with false-negative histories revealed no consistent features that would suggest such criteria. Sohn and Byers 19 have reviewed cost-effective drug screening and sugg e s t a selective approach to toxicologic analysis. They recommend that a substance should meet one or more of the following criteria to be considered for emergency analysis. Annals of Emergency Medicine
First, it should produce a potentially life-threatening intoxication. Second, signs and s y m p t o m s should be of rapid onset. Third, treatment m u s t be initiated early to prevent later complications. And finally, a specific antidote should exist. Acetaminophen meets three of four of these criteria; according to Sohn and Byers, this would indicate that the risk of inaccurate diagnosis based solely on clinical judgment is unacceptable. Acetaminophen is unique because of its lack of a specific recognizable syndrome that might suggest the diagnosis at a time early enough to result in life-saving antidotal intervention. Rapid serum acetaminophen determination is the only secure way to rule out the ingestion. In addition, rapid screening may allow earlier disposition of patients with insignificant a c e t a m i n o p h e n levels (who might otherwise have received NAC treatment unnecessarily) and earlier activated charcoal therapy in patients with mixed overdose (where concern about interference with oral NAC absorption may have delayed charcoal therapy). The cost to the hospital to run newer specific a c e t a m i n o p h e n assays such as the TDx is approximately $10 per sample. As we have d e m o n s t r a t e d , performing rapid acetaminophen levels in all drug overdose patients identified only one potentially treatable patient for every 500 patients screened. Some, however, feel it may be clinically justified to screen all overdose patients given the medical, legal, and financial consequences of a missed ingestion. This position remains controversial. CONCLUSION Acetaminophen is a commonly ingested drug and as many as 25% of patients with intentional drug overdose will volunteer that they have ingested it. Because rapid serum testing for serum acetaminophen is the only way to determine if treatment with the antidote NAC is needed and because the history of ingestion is frequently unreliable, m a n y physicians r o u t i n e l y order rapid s e r u m acetaminophen levels in all patients with drug overdose, regardless of the history. We have shown that in a busy urban ED setting, approximately one in 70 patients with drug overdose will have unsuspected acetaminophen in1037/29
ACETAMINOPHEN SCREENING Ashbourne, Olson & Khayam-Bashi
gestion, and approximately one in 500 will have unsuspected but potentially hepatotoxic levels that would only be identified by routine screening. G i v e n the low cost of newer rapid q u a n t i t a t i v e a c e t a m i n o p h e n methods, it may be clinically justified to screen all patients with drug overdose for aeetaminophen. Further studies will be needed to determine w h e t h e r this approach is a c t u a l l y cost effective, whether is applies to other ED patient populations, and w h e t h e r selective criteria can be e s t a b l i s h e d to l i m i t u n n e c e s s a r y screening.
We w i s h to a c k n o w l e d g e t h e a s s i s t a n c e of t h e s t a f f of t h e S a n F r a n c i s c o Bay A r e a R e g i o n a l P o i s o n C e n t e r (Drs B u c h a n a n , Brewer-Anderson, Joe, Keller, M c K i n n e y , Q u a n , Tani, a n d Woo); D r John O s t e r l o h , Toxicology Laboratory, San Francisco General Hospital; Dr Doug Dolingow, Toxicology Laboratory, H i g h l a n d G e n e r a l Hospital; a n d A b b o t t Laboratories.
REFERENCES 1. Davidson DGC, Eastham WN: Acute liver
necrosis following overdose of paracetamol. Br Med J 1966;2:497-499.
2. Litovitz TL, Schmitz B: 1986 Annual report of the AAPCC National Data Collection System. A m J Emerg Med 1987;5:405-445. 3. Piperno E, Berssenbruegge DA: Reversal of experimental paracetaruol toxicosis with Nacetylcysteine. Lancet 1976;2:738-740. 4. Peterson RG, R u m a c k BH: T r e a t m e n t of acute acetaminophen poisoning with N-acetylcysteine. JAMA 1977;237:2406-2407. 5. Rumack BH, Peterson RC, Koch GG, et al: Acetaminophen overdose: 662 cases with evaluation of oral acetylcysteine treatment. Arch Intern Med 1981;141:380-385. 6. Peterson RG, Rumack BH: Acetaminophen overdose: A high index of suspicion. Topics Emerg Med 1979;1:43-49. 7. Cohen 8B, Burk RF. Acetaminophen overdoses at a county hospital: A year's experience. South Med J 1978;71:1359-1363.
11. Galen RS: The predictive value model and patient care decisions, in Connelly DP, Benson ES, Burke MD, et al (eds): Clinical Decisions and Laboratory Use. Minneapolis, University of Minnesota Press, 1980. 12. Qirbi AA, Paznanski WJ: Emergency toxicology in a general hospital. CMA ] 1977;116: 884-888. 13. Soslow A: Acute drug overdose: One hospital's experience. Ann Emerg Med 1981;10:18-21. 14. Bailey DN, Manoguerra AS: Survey of drugabuse patterns and toxicology analysis in an emergency-room population. J A n a l Toxicol 1980;4:199-203. 15. Prescott LF, Roscoe P, Wright N, et al: Plasma paracetamol half-life and hepatic necrosis in patients with paracetamol overdose. Lancet 1971;1:519-522. 16. Linden CH: Antidotes in poisoning, in Callaham M {ed): Current Therapy in Emergency Medicine. Philadelphia, BC Decker, Inc, 1987, p 949.
8. Black M, Cornell JF, Rabin L, et al: Late presentation of acetaruinophen hepatotoxicity. Digest Dis Sci 1982;27:370-374.
17. Olson KR: Toxicology screens and asymptomatie poisoning, in Callaham M (ed): Current Therapy in Emergency Medicine. Philadelphia, BC Decker, Inc, 1987, p 946.
9. Keegan C, Smith C, Ungemach F, et al: A fluorescence polarization immunoassay for the quantitation of APAP (abstract). Clin Chem 1984;30:1025.
18. Kulig K, Bar-Or D, Cantrill SV, et al: Management of acutely poisoned patients without gastric emptying. A n n Emerg Med 1985;14: 562-567.
10. McCabe JB: Decision making in laboratory t e s t s t u d i e s . Emerg M e d Clin N or t h A m 1986;4:1-4.
19. Sohn D, Byers J: Cost-effective drug screening in t h e laboratory. Clin Toxicol 1981; 18:459-469.
See related editorial, p 1126
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Annals of Emergency Medicine
18:10 October 1989
Value of Rapid Screening for Acetaminophen in All Patients With Intentional Drug Overdose We performed a prospective study to determine the incidence of missed, potentially toxic acetaminophen poisoning in all patients with any type of intentional drug ingestion presenting to two large, county hospital emergency departments. Of 486 patients with drug ingestion seen during a fivem o n t h period, 114 (23.5%) were s u s p e c t e d of h a v i n g i n g e s t e d acetaminophen. Of these, 71 (62.3%) had insignificant acetaminophen levels (false-positive history). Of the 365 patients who were not suspected of having acetaminophen ingestion, seven patients (/.9%) were found to have elevated levels on rapid screening (false-negative history). Of these, only one patient had a potentially hepatotoxic level. We conclude that the incidence of missed, potentially serious acetaminophen overdose is very low in our study population. [Ashbourne JF, Olson KR, Khayam-Bashi H: Value of rapid screening for acetaminophen in all patients with intentional drug overdose. Ann Emerg Med October 1989;18:1035-1038.] INTRODUCTION Acetaminophen toxicity was first recognized in Great Britain in 1966 when Davidson and Eastham ~ described the acute hepatic and renal tubular necrosis associated with paracetamol (acetaminophen) overdose. Since the introduction of acetaminophen into widespread use in the United States, it has become one of the drugs most frequently ingested in cases reported to poison control centers. ~ Fortunately, an effective antidote (N-acetylcysteine, NAC) was discovered and is widely used in the management of acetaminophen overdose.3, 4 However, for NAC to be effective, it must be given within 12 to 16 hours after ingestion, s Acetaminophen intoxication has no recognizable specific clinical manifestations early in its course. Therefore, early diagnosis is based solely on the history and the serum acetaminophen concentration. 6 Because the history of ingestion is often unreliable or unavailable, Z,s there may be a delay in obtaining the serum acetaminophen concentration and a delay in recognition and treatment of the overdose; this may result in unnecessary morbidity or m o r t a l i t y . Thus, m a n y c l i n i c i a n s r o u t i n e l y order s e r u m acetaminophen determinations in all patients with intentional drug overdose, regardless of the history. However, no systematic study has been performed to evaluate this common practice. We performed a prospective study to determine the incidence of missed, potentially toxic acetaminophen poisoning in all patients with any type of intentional drug ingestion presenting to two large, urban county hospital emergency departments.
John F Ashbourne, MD, FACEP*t Kent R Olson, MD, FACEP*t Hassan Khayam-Bashi, MD~ Oakland, California San Francisco, California From the Department of Emergency Medicine, Highland General Hospital, Oakland, California;* the San Francisco Bay Area Regional Poison Control Center, San Francisco General Hospital;t and the Department of Laboratory Medicine, San Francisco General Hospital and the University of California, San Francisco. 4Received for publication March 2, 1988. Revisions received September 29, 1988, and May 30, 1989. Accepted for publication June 7, 1989. Partial funding (reagents) provided by Abbott Laboratories, Chicago, Illinois. Presented at the Annual Scientific Meetings of the American Association of Poison Centers/American Academy of Clinical Toxicology, Santa Fe, New Mexico, August 1986. Address for reprints: John F Ashbourne, MD, FACER Poison Control Centre, Foothills Hospital, 1403 29th Street NW, Calgary, Alberta, Canada T2N 2T9.
METHODS All patients 16 years and older who presented to the ED of Highland General Hospital or San Francisco General Hospital between February 1 and July 7, 1986, with any suspected or confirmed intentional drug ingestion were eligible for the study. Those with simple substance abuse (eg, nonsuicidal abuse of ethanol, cocaine, heroin) were excluded. Both hospitals are active university-affiliated teaching facilities with a combined annual ED census of more than 140,000. The study protocol received approval from the Committee on Human Research of the University of California, San Francisco, and the Human Subjects Protection Committee of
18:10October 1989
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ACETAMINOPHEN SCREENING Ashbourne, Olson & Khayam-Bashi
A l a m e d a County. All subjects received usual emergency care appropriate to their overdoses. As each patient was identified, a screening acetaminophen level was ordered immediately. Before receiving a report of the serum level, the patient's primary physician (attending or housestaff) was required to complete a brief questionnaire indicating whether acetaminophen ingestion was s u s p e c t e d and, if so, on what basis (Figure). Multiple choices were permitted. The physician was provided a choice on the questionnaire (selection E) that would indicate that he would routinely order acetaminophen screening regardless of the history. If this was the only choice selected on the questionnaire, this was considered a negative history. T h e p h y s i c i a n was told in advance the purpose of the study, m a x i m i z i n g the likelihood that a thorough history regarding acetaminophen ingestion would be obtained from the patient. When a patient with acetaminophen ingestion was identified through screening, routine care for acetaminophen overdose (including four-hour postingestion levels and NAC t r e a t m e n t , if indicated) was provided. Potentially hepatotoxic ser u m levels were identified by plotting the s e r u m level versus t i m e since i n g e s t i o n on the R u m a c k Matthew nomogram, s Serum acetaminophen determinations were performed on a stat basis at each facility using the TDx Therapeutic Drug Monitoring System (Abbott Laboratories, Chicago, Illinois). This system uses a fluorescence pol a r i z a t i o n i m m u n o a s s a y t h a t has minimal interference and a high degree of correlation with standard assays, i n c l u d i n g h i g h - p e r f o r m a n c e liquid chromatography. 9 In addition, it is inexpensive, fully automated, and can be performed in 15 minutes or less by a technician familiar with the procedure. (Test reagents were provided free of charge by Abbott Laboratories.) The limit of detection for this assay is 0.7 to 1.0 mg/L. To exclude t h e r a p e u t i c use or trivial overdose of acetaminophen we considered a serum level of less than 10 mg/L drawn within eight hours after ingestion to be clinically insignificant. C o m p l i a n c e w i t h the study was monitored at Highland Hospital on a 28/1036
FIGURE.
Study questionnaire.
daily basis by reviewing all ED charts from the previous day. Monitoring was accomplished at San Francisco General Hospital by reviewing Drug Abuse Warning N e t w o r k (DAWN) s u m m a r i e s of all drug-related ED visits and chart review of each overdose case. At San Francisco General Hospital, DAWN summaries are prepared daily by experienced poison center staff and are considered reliable screening for drug-related ED visits. Standard formulae were used for calculation of sensitivity, specificity, and positive and negative predictive values. ~o,11 RESULTS
During the five-month study period, 486 patients were included in the study - 211 from Highland General Hospital and 275 from San Francisco General Hospital (Table). Of these, 476 were identified prospectively, and ten were discovered later on retrospective chart review. During the same period, 101 eligible patients with drug ingestion were seen in the two EDs but were not included in the study, giving an overall compliance of 486 of 587 (83%). These 101 patients were eligible for the study but were o v e r l o o k e d for e n t r y by the treating physicians. They were not purposely excluded from the study. On review of their hospital charts, we could not find any patient in this group who had a missed acetaminophen overdose based on toxicological screen, hospital clinical course, or subsequent ED Visits. There were 365 patients (75.1%) with no suspected acetaminophen' ingestion who were found to have insignificant s e r u m a c e t a m i n o p h e n concentrations (less than 10 rag/L); these patients were defined as having a true-negative history. Forty-three p a t i e n t s (8.8%) were suspected of having ingested acetaminophen and were found to have elevated (more than 10 mg/L) serum acetaminophen levels; these patients were considered to have a true-positive history. Seventy-one patients (14.6%) had a h i s t o r y of acetaminophen ingestion but were found to have insignificant (less than 10 rag/L) acetaminophen levels; these were described as having a false-positive history. Finally, Annals of Emergency Medicine
Do you suspect acetaminophen ingestion in this patient? If yes, indicate why (more than one choice permitted): A B C D E
History from patient History from witness Pill bottles Clinical syndrome Standard screening test you use in your emergency practice
seven patients (1.4%) had no history or suspicion of acetaminophen ingestion but had elevated serum acetaminophen levels; these were considered false-negative histories. The sensitivity, specificity, and positive and negative predictive values of the history as a predictor of acetaminophen ingestion are shown (Table). Of the seven cases in which the history was falsely negative, only one p a t i e n t - a 41-year-old H i s p a n i c woman who presented with a history of diazepam ingestion - had what could be considered a p o t e n t i a l l y hepatotoxic level. Although she had also ingested acetaminophen (Tylenol ® and Excedrin PM®), this history was not initially obtained because she spoke no English. Her acetaminophen intoxication was discovered only after her screening level was reported as 196 mg/L (obtained 11 to 12 hours after ingestion). She was treated with NAC and recovered without complications. The other six patients with falsenegative history for acetaminophen ingestion had serum levels ranging from 14 to 104 rag/L; none were in the toxic range when plotted against time since ingestion on the standard c o n c e n t r a t i o n - t i m e n o m o g r a m . In none of these six cases was there an apparent reason for the false-negative history (ie, language barrier, confusion, or coma). All six patients were treated appropriately, and none developed hepatotoxicity. In 139 of the 486 patients (29%), the physician completing the questionnaire selected only E, indicating that despite a negative history, the physician would routinely screen for a c e t a m i n o p h e n . In all but one of these, the acetaminophen screen was negative (false-negative rate, 0.7%). 18:10 October 1989
TABLE. Results Highland General Hospital (%) True-negatives True-positives False-positives False-negatives Total cases Sensitivity of the history Specificity of the history Positive predictive value Negative predictive value
167 (79) 16 (8.6) 26 (12.3) 2 (1.0) 211 = .86 = .84 = .38 = .99
(Because the n u m b e r of physicians completing the questionnaires was very large and the participating physicians comprised a varied group of rotating residents and attending physicians, it was not possible to make any conclusions about the characteristics of the group choosing E on the questionnaire.) Laboratory turnaround times were available for 139 of the p a t i e n t s (66%) at Highland General Hospital. The average time to complete the assay from receipt of the specimen was 46 minutes. The most significant delay in performing the test was in obtaining the sample and transporting it to the laboratory. DISCUSSION Acetaminophen is a commonly ingested drug found in a variety of prescription and over-the-counter products. As our study indicates, an urban ED may expect that as many as 25% of its overdose p a t i e n t s will have i n g e s t e d a c e t a m i n o p h e n or claim to have done so. To screen these patients, it is essential that a reliable, rapid, quantitative test for a c e t a m i n o p h e n be available for a busy ED. The question is, should all drug-overdose p a t i e n t s r o u t i n e l y have a rapid a c e t a m i n o p h e n determination, regardless of the history of ingestion? The history of drug ingestion is frequently unreliable, 12-14 and determination of ingested drugs on purely clinical grounds may B~ difficult, especially in the case of acetaminophen. 6 Previous case reports have demonstrated that because of unreliable or u n a v a i l a b l e history, aceta m i n o p h e n i n g e s t i o n m a y be 18:10 October 1989
San Francisco General Hospital (%) 198 27 45 5 275
(72) (9.8) (16.4) (1.8)
Total (%) 365 43 71 7 486
(75) (8.8) (14.6) (1.4) (100)
missed, Z,8 and serious toxicity m a y e n s u e b e c a u s e t r e a t m e n t is delayed.S, 15 Because early recognition of a c e t a m i n o p h e n i n t o x i c a t i o n is necessary for proper antidotal treatment, m a n y physicians and poison centers now frequently recommend routine rapid acetaminophen levels in all patients with intentional drug overdose, regardless of history. 16,17 However, until now, this approach has never been subjected to serious study. We have d e m o n s t r a t e d that approximately one in 70 patients who presents with intentional drug ingestion to an urban general hospital ED will have unrecognized acetaminophen overdose, and approximately one in 500 will have potentially hepatotoxic levels. This finding is consistent with an earlier study of unselected drug overdoses is in which the only death in 592 consecutive cases was an unrecognized acetaminophen ingestion. These ratios m a y not apply to all ED patient populations. In other ED populations, patients m a y be m o r e reliable historians or may have a lower likelihood of a language barrier as a cause of an inaccurate history. Further studies m a y establish selective criteria for acetaminophen screening; however, a review of our seven patients with false-negative histories revealed no consistent features that would suggest such criteria. Sohn and Byers 19 have reviewed cost-effective drug screening and sugg e s t a selective approach to toxicologic analysis. They recommend that a substance should meet one or more of the following criteria to be considered for emergency analysis. Annals of Emergency Medicine
First, it should produce a potentially life-threatening intoxication. Second, signs and s y m p t o m s should be of rapid onset. Third, treatment m u s t be initiated early to prevent later complications. And finally, a specific antidote should exist. Acetaminophen meets three of four of these criteria; according to Sohn and Byers, this would indicate that the risk of inaccurate diagnosis based solely on clinical judgment is unacceptable. Acetaminophen is unique because of its lack of a specific recognizable syndrome that might suggest the diagnosis at a time early enough to result in life-saving antidotal intervention. Rapid serum acetaminophen determination is the only secure way to rule out the ingestion. In addition, rapid screening may allow earlier disposition of patients with insignificant a c e t a m i n o p h e n levels (who might otherwise have received NAC treatment unnecessarily) and earlier activated charcoal therapy in patients with mixed overdose (where concern about interference with oral NAC absorption may have delayed charcoal therapy). The cost to the hospital to run newer specific a c e t a m i n o p h e n assays such as the TDx is approximately $10 per sample. As we have d e m o n s t r a t e d , performing rapid acetaminophen levels in all drug overdose patients identified only one potentially treatable patient for every 500 patients screened. Some, however, feel it may be clinically justified to screen all overdose patients given the medical, legal, and financial consequences of a missed ingestion. This position remains controversial. CONCLUSION Acetaminophen is a commonly ingested drug and as many as 25% of patients with intentional drug overdose will volunteer that they have ingested it. Because rapid serum testing for serum acetaminophen is the only way to determine if treatment with the antidote NAC is needed and because the history of ingestion is frequently unreliable, m a n y physicians r o u t i n e l y order rapid s e r u m acetaminophen levels in all patients with drug overdose, regardless of the history. We have shown that in a busy urban ED setting, approximately one in 70 patients with drug overdose will have unsuspected acetaminophen in1037/29
ACETAMINOPHEN SCREENING Ashbourne, Olson & Khayam-Bashi
gestion, and approximately one in 500 will have unsuspected but potentially hepatotoxic levels that would only be identified by routine screening. G i v e n the low cost of newer rapid q u a n t i t a t i v e a c e t a m i n o p h e n methods, it may be clinically justified to screen all patients with drug overdose for aeetaminophen. Further studies will be needed to determine w h e t h e r this approach is a c t u a l l y cost effective, whether is applies to other ED patient populations, and w h e t h e r selective criteria can be e s t a b l i s h e d to l i m i t u n n e c e s s a r y screening.
We w i s h to a c k n o w l e d g e t h e a s s i s t a n c e of t h e s t a f f of t h e S a n F r a n c i s c o Bay A r e a R e g i o n a l P o i s o n C e n t e r (Drs B u c h a n a n , Brewer-Anderson, Joe, Keller, M c K i n n e y , Q u a n , Tani, a n d Woo); D r John O s t e r l o h , Toxicology Laboratory, San Francisco General Hospital; Dr Doug Dolingow, Toxicology Laboratory, H i g h l a n d G e n e r a l Hospital; a n d A b b o t t Laboratories.
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2. Litovitz TL, Schmitz B: 1986 Annual report of the AAPCC National Data Collection System. A m J Emerg Med 1987;5:405-445. 3. Piperno E, Berssenbruegge DA: Reversal of experimental paracetaruol toxicosis with Nacetylcysteine. Lancet 1976;2:738-740. 4. Peterson RG, R u m a c k BH: T r e a t m e n t of acute acetaminophen poisoning with N-acetylcysteine. JAMA 1977;237:2406-2407. 5. Rumack BH, Peterson RC, Koch GG, et al: Acetaminophen overdose: 662 cases with evaluation of oral acetylcysteine treatment. Arch Intern Med 1981;141:380-385. 6. Peterson RG, Rumack BH: Acetaminophen overdose: A high index of suspicion. Topics Emerg Med 1979;1:43-49. 7. Cohen 8B, Burk RF. Acetaminophen overdoses at a county hospital: A year's experience. South Med J 1978;71:1359-1363.
11. Galen RS: The predictive value model and patient care decisions, in Connelly DP, Benson ES, Burke MD, et al (eds): Clinical Decisions and Laboratory Use. Minneapolis, University of Minnesota Press, 1980. 12. Qirbi AA, Paznanski WJ: Emergency toxicology in a general hospital. CMA ] 1977;116: 884-888. 13. Soslow A: Acute drug overdose: One hospital's experience. Ann Emerg Med 1981;10:18-21. 14. Bailey DN, Manoguerra AS: Survey of drugabuse patterns and toxicology analysis in an emergency-room population. J A n a l Toxicol 1980;4:199-203. 15. Prescott LF, Roscoe P, Wright N, et al: Plasma paracetamol half-life and hepatic necrosis in patients with paracetamol overdose. Lancet 1971;1:519-522. 16. Linden CH: Antidotes in poisoning, in Callaham M {ed): Current Therapy in Emergency Medicine. Philadelphia, BC Decker, Inc, 1987, p 949.
8. Black M, Cornell JF, Rabin L, et al: Late presentation of acetaruinophen hepatotoxicity. Digest Dis Sci 1982;27:370-374.
17. Olson KR: Toxicology screens and asymptomatie poisoning, in Callaham M (ed): Current Therapy in Emergency Medicine. Philadelphia, BC Decker, Inc, 1987, p 946.
9. Keegan C, Smith C, Ungemach F, et al: A fluorescence polarization immunoassay for the quantitation of APAP (abstract). Clin Chem 1984;30:1025.
18. Kulig K, Bar-Or D, Cantrill SV, et al: Management of acutely poisoned patients without gastric emptying. A n n Emerg Med 1985;14: 562-567.
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19. Sohn D, Byers J: Cost-effective drug screening in t h e laboratory. Clin Toxicol 1981; 18:459-469.
See related editorial, p 1126
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Annals of Emergency Medicine
18:10 October 1989