DOI: 10.1542/peds.2011-2345; originally published online January 23, 2012; 2012;129;349Pediatrics

Richard C. Dart and Barry H. RumackIntravenous Acetaminophen in the United States: Iatrogenic Dosing Errors

  

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of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2012 by the American Academy published, and trademarked by the American Academy of Pediatrics, 141 Northwest Pointpublication, it has been published continuously since 1948. PEDIATRICS is owned, PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

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Intravenous Acetaminophen in the United States:Iatrogenic Dosing Errors

abstractAn intravenous formulation of acetaminophen was introduced to theUnited States in 2011. Experience from Europe indicates that seriousdosing errors are likely to occur. Most events have involved a 10-folddosing error in small children caused by calculating the dosage inmilligrams, but then administering the solution in milliliters. The so-lution is 10 mg/mL; therefore, a 10-fold overdose occurs. Evaluation ofoverdose with the intravenous formulation is similar to oral overdose.A serum acetaminophen concentration should be drawn 4 hours afterthe infusion was started or as soon thereafter as possible. If the serumacetaminophen concentration plots above the treatment line on theRumack-Matthew nomogram, treatment with acetylcysteine shouldbe initiated. Health care providers are encouraged to contact their re-gional poison center (1-800-222-1222) so that dosing errors will bereported, and the experience with this new product can be accumu-lated. Pediatrics 2012;129:349–353

AUTHORS: Richard C. Dart, MD, PhD,a,b and Barry H.Rumack, MDa,c

aRocky Mountain Poison and Drug Center, Denver Health, Denver,Colorado; Departments of bEmergency Medicine and cPediatrics,University of Colorado School of Medicine, Denver, Colorado

KEY WORDSacetaminophen, paracetamol, adverse event, intravenousadministration, human

ABBREVIATIONNAPQI—n-acetyl-p-benzoquinoneimine

Drs Dart and Rumack participated in the conception, writing,revision, and final approval of the article.

www.pediatrics.org/cgi/doi/10.1542/peds.2011-2345

doi:10.1542/peds.2011-2345

Accepted for publication Oct 24, 2011

Address correspondence to Richard C. Dart, MD, Denver HealthMedical Center, Rocky Mountain Poison and Drug Center, 777Bannock St # 180, Denver, CO 80204. E-mail: richard.dart@rmpdc.org

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2012 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE: Drs Dart and Rumack were part ofa group of consultants retained by Cadence Pharmaceuticals todevelop recommendations for management of overdose of IVacetaminophen.

PEDIATRICS Volume 129, Number 2, February 2012 349

SPECIAL ARTICLE

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The US Food and Drug Administrationrecently approved the intravenouspreparation of acetaminophen formanagement of fever and moderateacute pain.1 The intravenous product isapproved for use in all ages in manycountries, but is not approved for usein children ,2 years of age in theUnited States. Nevertheless, off-labeluse can be anticipated, because it isused in young children internationally,and this age group often has difficultywith oral administration. Over 500million doses have been distributedworldwide since 2002. The US Food andDrug Administration-approved dosingregimens are slightly different thanoral acetaminophen (Table 1).

Although this product is used in thecontrolled conditions of a hospital, iat-rogenic medication error events havebeen reported. In 2010, the UnitedKingdom Medicines and Healthcare pro-ducts Regulatory Agency reported thatmost overdose errors involved a 10-fold

dosing error in young children causedby calculating the dosage inmilligrams,but then administering the solution inmilliliters.2 The solution is 10 mg/mL;therefore, a 10-fold overdose occurs.The product distributed in the UnitedStates is also 10 mg/mL (Ofirmev, Ca-dence Pharmaceuticals, San Diego, CA).Pediatricians, particularly pediatrichospitalists and intensivists, will nowface similar challenges in the UnitedStates.

TheMedicines andHealthcare productsRegulatory Agency safety report noted23 cases of single or repeated dosingerrors with intravenous acetamino-phen in children,1 year of age, one ofwhich was fatal.2 A single infusion ofa 10-fold overdose was reported inmost of these cases. Searches ofMedline and the Web and queries topoison center directors in Europeidentified three patients with a singleoverdose infusion reported in themedical literature (Table 2).3,4 All three

cases occurred after surgery and in-volved a single iatrogenic dosing errorranging from 75 to 146 mg/kg. Theinitial serum acetaminophen concen-trations did not qualify for treatmentbased on the acetaminophen nomo-gram used in the United States.

One of the cases developed liver injurywith a reported dose of 75 mg/kg,raising the specter of liver toxicitywith a serum concentration far belowthe treatment line on the Rumack-Matthew nomogram.3 The authors re-commended a threshold of 60 mg/kg toinitiate acetylcysteine treatment inpatients experiencing acute intrave-nous overdosage. This recommenda-tion seems very low considering thatyoung children are considered re-sistant to acetaminophen toxicity andauthorities have suggested that theycan tolerate larger amounts of acet-aminophen than adults.5 For example,consensus-based triage guidelines foringestion of acetaminophen in childrenrecommend that a child should be re-ferred to a health care facility only af-ter the acetaminophen dose exceeds200 mg/kg.6 The report also includesinformation that casts doubt on acet-aminophen as the cause of liver injury(Table 2). The child’s acetaminophen con-centration at 6 hours after the infusion

TABLE 1 Recommended Dosing of Intravenous Acetaminophen1

Children $ 2-to 12-y-old

Adults and AdolescentsWeighing ,50 kg

Adults and AdolescentsWeighing $50 kg

Single dose 15 mg/kg every 6 hOR12.5 mg/kg every 4 h

15 mg/kg every 6 hOR12.5 mg/kg every 4 h

1000 mg every 6 hOR650 mg every 4 h

Maximum daily dose 75 mg/kg per day 75 mg/kg per day 4000 mg per dayMinimum dosing interval 4 h 4 h 4 h

TABLE 2 Intravenous Acetaminophen Overdose Case Reports

Reference PatientDetails

Acetaminophen dose, mg/kg Serum AcetaminophenTime from Infusion:

mg/mL

Laboratory AcetylcysteineTreatment

3 Age 5 mo (6.9 kg) F,shock from necroticileocolic intussusception

75 6 h: 38 6 h after infusion:ALT 61 IU/L, bilirubin

1.7 mg/dL (normal upto 1.0 mg/dL)

34–48 h after infusion:ALT 2819 IU/Lbilirubin 2.0 mg/dLINR 3.6

Started 24 h afterinfusion andcontinued 4 d

3 6 mo (4.0 kg) M, 8 wkpremature and developingwell; inguinal hernia repair

75.8 1 h: 724 h: 35

Day after infusion:“normal liver function tests”

Started “immediately”and continued 20 h

4 7 wk M; inguinal hernia repair 146 4 h: 1178 h: 72

36 h: , 1

Normal aminotransferaselevels and bilirubin

Highest INR 1.27

Started within 4 h ofinfusion andcontinued 20 h

ALT, alanine aminotransferase; F, female; INR, international normalized ratio; M, male.

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was 38 mg/L, well below the treatmentnomogram line, and the bilirubin andaminotransferase levels were alreadyincreased—a much more rapid evolu-tion than expected for acetaminophen-inducedhepatotoxicity.7Most importantly,the child had clinical signs of shockthat required resuscitation and thenhad intraabdominal surgery, all beforethe infusion of acetaminophen. There-fore, ischemic liver injury is a plausiblealternative explanation for the elevatedtests.8 The occurrence of a singleclinically complicated case of hepati-tis that was preceded by hypotensionand intraabdominal surgery is notsufficient to alter management of IVacetaminophen dosing errors.

DIFFERENCES BETWEEN ORAL ANDINTRAVENOUS OVERDOSAGE

There are differences between oral andintravenous exposure to acetamino-phen. Oral administration results in apeak concentration an hour or moreafter ingestion; the acetaminophen con-centrationmaycontinue rising forhoursafter a large oral overdose. In contrast,intravenousadministrationproducesanimmediate peak, but the concentrationdeclines rapidly.9 The higher peak con-centration after intravenous adminis-tration may seem to imply greatertoxicity. However, many overdose in-gestions produce similar or even higherpeak serum concentrations and aremanaged successfully with the currentnomogram approach.

Gastrointestinal absorption of acet-aminophen occurs primarily throughthe splanchnic circulation. This routeproduces high hepatic concentrationsof acetaminophen. Since acetamino-phen is metabolized to its toxic me-tabolite n-acetyl-p-benzoquinoneimine(NAPQI) in the liver, the oral routeprovides the most drug for productionof NAPQI. After intravenous infusion,serum concentrations are high, butpharmacokinetic modeling indicates

that the hepatic exposure may be lessbecause it avoids the large first-passeffect of ingestion. In theory, moreacetaminophen would therefore un-dergo metabolism to NAPQI after in-gestion compared with intravenousinfusion. Based on modeling, intra-venous infusion is predicted to producea peak acetaminophen concentrationin the liver 50% less than the concen-tration produced by the same oraldose.10 Therefore, it is highly unlikelythat administration of a 10-fold over-dose through the intravenous routewould produce more of the toxic me-tabolite. It might well produce less ofthe metabolite.

EVALUATION AND MANAGEMENT OFINTRAVENOUS ACETAMINOPHENDOSING ERRORS

The time of the error will be accuratelyknown in many cases because it wasadministered in a health care facility.Safety reports indicate that the error istypically discovered when the subse-quent dose of acetaminophen is aboutto be administered.

If the dose of acetaminophen infused isknown to be,150 mg/kg after a singledosing error, no further evaluation isneeded. If the amount infused couldexceed 150 mg/kg or there is doubtabout the exact amount administered,a serum acetaminophen concentrationis obtained at 4 hours after adminis-tration or as soon as possible thereaf-ter. The acetaminophen concentration isplotted against the time elapsed sinceacetaminophen administration. If theserum level is above the treatment line,a complete course of N-acetylcysteinetreatment is recommended. The timethat the sample was drawn should benoted carefully, because, frequently,the blood is not actually drawn until anhour or more after it was ordered. Be-cause the serum acetaminophen levelfalls more quickly after intravenousadministration than after ingestion,

the time difference could lead to sub-stantial underestimation of the se-verity of overdosage.

The method described in the productlabeling is appropriate for young chil-dren.1 It describes a management ap-proach similar to oral overdose. Theclinical experience available regardingacute acetaminophen ingestion in youngchildren is extensive because overdoseoccurs several thousand times peryear in the United States. The Rumack-Matthew nomogram has been usedto manage myriad permutations ofpediatric overdose over the past 40years. Physicians are familiar with thediagnostic approach. Nurses and phar-macists are familiar with adminis-tration of the antidote, acetylcysteine.An extensive array of clinical condi-tions, including a massive dose, variouscoingestants, and a variety of under-lying diseases, have been addressedby clinicians and researchers nation-ally and internationally. The nomogramis a robust tool with a generous marginof error.

When can acetaminophen be restartedin a young child that has experienceda medication error? If the serum acet-aminophen concentration is below thenomogram treatment line (the linebeginning at 150mg/mLat 4 hours afterinfusion), acetaminophen could berestarted once the serum concentra-tion has fallen to below 10mg/L and theserum alanine aminotransferase levelis normal. If the child experienced liverinjury, acetaminophen should withhelduntil the acetaminophen concentrationis ,10 mg/L, the alanine aminotrans-ferase level has returned to baselinefor the child and the liver shows clearevidence of synthetic activity (pro-thrombin time or international nor-malized ratio are normal without theneed of blood product support).

In some cases, a medication error hasbeen discovered immediately afterinfusion, raising the issue of how to

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evaluate the potential for toxicity whena blood level has been drawn within anhour or two of the infusion. Serumacetaminophen concentrations obtainedbefore 4 hours after an oral acetamin-ophen overdose cannot be plotted on theacetaminophen nomogram becausestudies have shown that early serumconcentrations do not reliably predictacetaminophen concentration on thenomogram after ingestion. Becauseacetaminophen infusion produces ear-lier peak concentrations, it is plausiblethat earlier concentrations would bemedically useful. Preliminary data frompharmacokinetic modeling indicate thatextrapolation of the current nomogramline to 1 or 2 hours after infusion maybe possible in the case of intravenousacetaminophen dosing errors.10 How-ever, this technique cannot be rec-ommended until further researchdocuments its effectiveness.

Furthermore, accurate knowledge ofthe dose may eventually allow for analternate treatment approachbased onthe dose itself rather than a serumacetaminophen concentration plottedon the nomogram. After ingestion, thedose is not used to assess the need fortreatment because of inaccuracies inthe history. The dose is usually knownaccurately after intravenous adminis-tration. Assuming 100% bioavailabilityof an intravenous 150 mg/kg dose ina 10-kg child with an acetaminophenvolume of distribution of 1 L/kg (the Vdreported for neonates and infants is 1.16 0.3 L/kg),1 the predicted serumacetaminophen concentration wouldbe ∼150 mg/L, which is the acetamin-ophen concentration threshold on thenomogram at 4 hours for treatmentwith acetylcysteine. Therefore, it may be

logical to initiate N-acetylcysteine afteran intravenous acetaminophen dose of150mg/kg or greater, because thismayresult in a concentration reaching thetreatment line on the acetaminophennomogram. Currently, this is a theoret-ical extrapolation, and a serum acet-aminophen level should still be drawnat 4 hours.

Another concern involves the treatmentof overdose in neonates. Few oraloverdoses have been reported in neo-nates. Neonates exhibit a longer elimi-nationhalf-life andagreaterareaunderthe curve after intravenous adminis-tration than after oral dosage, implyingthat they have slower metabolism andlonger exposure to acetaminophen.1

However, neonates and infants havebeen shown to have reduced concen-trations of cytochrome P-450 IIE1, themain enzyme responsible for generat-ing the toxic metabolite of acetamino-phen.11 Furthermore, the primarydefense against acetaminophen injury,glutathione, reaches concentrationssimilar to adults early in deve-lopment.12 Thus, neonates would alsobe expected to have reduced risk fromacetaminophen medication errorssimilar to infants and young children.Given the paucity of information avail-able, it is recommended that a regionalpoison center or clinician experiencedin the treatment of acetaminophenoverdose be consulted in such cases.

CONCLUSIONS

Hospitalists and intensivists can an-ticipate cases of iatrogenic dosingerrors of intravenous acetaminophenin young children. Proactive consulta-tion with your hospital’s department of

pharmacy and nursing staff when thisproduct is added to the formularywould raise awareness of this potentialerror and could prevent dosing errors.For example, clinicians should writethe dose in both milligrams and inmilliliters to prevent confusion of theamount with the volume. Once a medi-cal error has been discovered, theestablished management of acuteoral overdose by using the Rumack-Matthew nomogram is an appropriatestrategy for managing most of thesecases. When a dosing error is discov-ered soon after the infusion, however,it may be reasonable to initiate treat-ment if the dose reaches 150 mg/kg,because that dose may produce a se-rum acetaminophen concentrationabove the nomogram treatment line. Aserum acetaminophen concentrationshould still be drawn at 4 hours afterinfusion. Clinical experience of acet-aminophen overdose in neonates isvery limited, and close management ofthese patients is recommended. Untilmore experience is acquired with theintravenous formulation, consultationwith a poison center (1-800-222-1222)or clinician experienced in the treat-ment of acetaminophen overdose isrecommended. Issues such as con-current illness or concomitant medica-tions as well as simple documentationin the national database of these newpoisonings would be useful. Carefulepidemiology is required, as the use ofthe product expands to provide a betterprofile on the associated medicationerrors and their management.

ACKNOWLEDGMENTWe thank Luke Yip, MD, for his inspira-tion regarding the need for this article.

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6. Dart RC, Erdman AR, Olson KR, et al;American Association of Poison Control Cen-ters. Acetaminophen poisoning: an evidence-based consensus guideline for out-of-hospitalmanagement. Clin Toxicol (Phila). 2006;44(1):1–18

7. Green TJ, Sivilotti ML, Langmann C, et al.When do the aminotransferases rise afteracute acetaminophen overdose? Clin Tox-icol (Phila). 2010;48(8):787–792

8. Jacquemin E, Saliba E, Blond MH, ChantepieA, Laugier J. Liver dysfunction and acutecardiocirculatory failure in children. Eur JPediatr. 1992;151(10):731–734

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11. Vieira I, Sonnier M, Cresteil T. Developmentalexpression of CYP2E1 in the human liver.Hypermethylation control of gene expressionduring the neonatal period. Eur J Biochem.1996;238(2):476–483

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CALL CENTER HELP: The other day I tried to make a hotel reservation. I called thehotel’s central reservation number and after telling one person where I wanted tostay, I was switched to another operator. It became readily apparent that the newreservations clerk was not located in the United States. I explained that I wantedto spend a single night at their Burlington, Vermont hotel. We went back on forthon this topic for about five minutes. After being offered a room in New Hampshire,southern Vermont, Idaho, and New York I finally thanked him for his efforts andtold him I would seek an alternative arrangement. We both spoke English butquite differently. Also, he had no idea if Burlington was a city or a state and whatthe devil Vermont had to do with the address. According to an article in The NewYork Times (Business: November 25, 2011), companies have learned that not allEnglish is the same. When companies began setting up off-shore call centers,most were located in India where there is a huge English speaking population.However, Indians learn British English and are not as familiar with Americanphrases, phrasing, and culture. Over the past several years, companies havebeen relocating to the Philippines and nowmore call center agents are located inthe Philippines than India. While wages in the Philippines are a little higher, theadvantage is that Filipinos speak American English. Many are steeped in Amer-ican culture having grown up watching American television, eating at fast foodfranchises, and rooting for American basketball teams. Accents tend to be lightand hard to place and companies receive fewer complaints that the customerscannot understand the call center operators. Of course, many would argue thatoutsourcing call center jobs hurts Americans. Whether as part of agreementswith unions or because of angry customers, some large companies, includingairlines have moved their call centers back to the U.S. Recently, I purchaseda piece of electronic equipment and the salesman tried to get me to buy theextended warranty. His argument was that the call center was in New Jersey andnot only would I speak to someone who spoke excellent English but I would besupporting American jobs. As for me, I called the hotel directly to book my res-ervation. While I was again re-routed to a distant site, the reservation clerk and Iunderstood each other quite well and I was able to quickly confirm a lovely roomwith a view of Lake Champlain.

Noted by WVR, MD

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DOI: 10.1542/peds.2011-2345; originally published online January 23, 2012; 2012;129;349Pediatrics

Richard C. Dart and Barry H. RumackIntravenous Acetaminophen in the United States: Iatrogenic Dosing Errors

  

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