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The Acetaminophen Toxicity Equations: “Solutions” for Acetaminophen Toxicity Based on the Rumack-Matthew Nomogram

co-opted into advocacy for the patient; such representatives may
protest that presently or in the future there may be a serious or
even life-threatening illness, the treatment of which may be
compromised by a limit-setting approach. This provides the
staff with an opportunity to advise the patient that he may
indeed jeopardize his future health and care by present excesses.
The management plan should be included in the patient’s
record. Coordination with other agencies is important and may
require only a telephone call or a brief conversation with those
who accompany the patient. These tools may assist emergency
staffs in containing these difficult patients, while enabling them
to live without chaos and to minimize occurrences of acting out.
James L. Elmore, MD
Coastal Empire Community Mental Health Center
Beaufort, SC
The Acetaminophen Toxicity Equations:
‘‘Solutions’’ for Acetaminophen Toxicity
Based on the Rumack-Matthew Nomogram
To the Editor:
Acetaminophen, alone and with opiates and other
coingestants, is the most frequently implicated agent reported
in exposures to the American Association of Poison Control
Centers Toxic Exposure Surveillance System.
initially reported in the United Kingdom, an increase in the
frequency of acetaminophen overdose was recognized in the
United States in the mid-1970s, leading to the National
Multi-Clinic Open Trial of N-acetylcysteine.
The Rumack-Matthew nomogram for acetaminophen
toxicity (Figure 1), first published in 1975 and referred to as
the ‘‘200 line,’’ was derived from acetaminophen levels from
untreated patients; the ‘‘200 line’’ predicted outcome by
dividing patients who did and who did not develop an
aspartate aminotransferase level of 1,000 IU/L or greater in
relationship to their first acetaminophen level.
The ‘‘150
line’’ was developed as the study design line in the multiclinic
N-acetylcysteine trial and was published in 1981
; the ‘‘150
line’’ remains the lower treatment line for considering
N-acetylcysteine therapy. An outcome nomogram demonstrat-
ing the results of treated patients and using the ‘‘200 and
150 lines’’ has been published to further improve clinical
prediction and decisionmaking and to validate the
nomogram lines.
The Rumack-Matthew nomogram can easily be defined
mathematically, even though the nomogram lines are plotted
on a semilogarithmic graph and describe nonlinear relation-
ships. The equations representing the lines of the nomogram
can then enable the determination of the potential toxic level
of acetaminophen for any time after ingestion.
The general equation for a line, using 2 points P
=(x1, y1)
and P
=(x2, y2) is: yy1¼mðxx1Þwhere the slope,
For the nomogram ‘‘200 line’’ (probable toxicity), we can
consider the y-axis to be represented linearly by the Log
the acetaminophen level (log A
,mg/mL) and the x-axis to
be represented by time (t, hr). If we use the original data points
that generated the ‘‘200 line,’’ that is, Point P
=(log 200,
4 hr) and Point P
=(log 50, 12 hr), the equation becomes:
logAtox log200 ¼log50 log200
12 4ðt4Þ
Solving the numeric portions and isolating the unknown
variable yields:
logAtox 2:30103 ¼ð0:075257Þðt4Þ
logAtox ¼ð0:075257tÞþð4Þð0:075257Þ
þ2:30103 ¼ð0:075257tÞþ2:602058
Finding the antilog of each side of the equation and
10ðlogAtox Þ¼10ð2:6020580:075257tÞ
Atox ¼ÿ102:602058ð100:075257 Þt
The equation for the ‘‘200 line’’ then becomes:
Atox ¼400:00ð0:840897Þt400ð0:84Þt
The equation for the ‘‘150 line’’ for N-acetylcysteine
treatment for known time of acetaminophen ingestion is simply
a 25% reduction:
ANAC ¼300ð0:840897Þt
ANAC ¼300ð0:84Þt
where A
is the acetaminophen level in mg/mL above which
treatment with N-acetylcysteine may be warranted, and
tis time in hours elapsed from ingestion to acetaminophen
The validity of the equations can be demonstrated by
substituting the original times from which the equations were
derived (t=4 hr and t=12 hr). Using the more precise equation
for the ‘‘200 line,’’ using 0.840897 to the power of t, yields
200.00 mg/mL and 50.00 mg/mL, respectively, whereas the
approximated equation using 0.84 gives values of 199.15 mg/
mL and 49.36 mg/mL. This difference is clinically insignificant,
given the usual approximations of the time of ingestion and
draw time of the acetaminophen level.
Finally, when ingestion time is uncertain but an approximate
range of times is known, the equation can be solved for time
Volume 45, no. 5 : May 2005 Annals of Emergency Medicine 563
tin terms of acetaminophen level Ato determine the earliest
time that an acute ingestion could have been taken without
likely toxicity, given a measured level of acetaminophen:
t¼32:9155 13:2878ðlog AÞ
t¼33 13:3ðlog AÞ
where Ais measured acetaminophen level in mg/mL and
tis time interval in hours, within which acetaminophen level
is likely to be nontoxic.
The simplified versions of these 2 equations are relatively
easy to memorize and can be solved on any calculator with
‘‘x^y’’ (x to the y power) and ‘‘log’’[log-base 10] keys. Such
a calculator is available on any computer running under the
Windows (Microsoft Corporation, Redmond, WA) operating
system (Figure 2). In addition, the precise forms of the
equations can be used within a computer spreadsheet or can be
programmed into a handheld personal digital assistant. The
equations can also be incorporated within a hospital’s in-
formatics system in such a way that customized treatment
guidelines could be reported to the clinician in conjunction with
the acetaminophen laboratory results. However, as with the
Rummack-Matthew nomogram, these equations should not
substitute for judicious consultation
with a regional poison control center.
Steven J. White, MD
Departments of Emergency Medicine and Pediatrics
Vanderbilt University Medical Center
Nashville, TN
Barry H. Rumack, MD
Rocky Mountain Poison and Drug Center
University of Colorado School of Medicine
Denver, CO
1. Watson WA, Litovitz TL, Rodgers GC, et al. 2002 Annual Report
of the American Association of Poison Control Centers Toxic
Exposure Surveillance System. Am J Emerg Med. 2003;21:
2. Rumack BH, Peterson RC, Koch GC, et al. Acetaminophen overdose:
662 cases with oral acetylcysteine therapy. Arch Intern Med. 1981;
3. Smilkstein MJ, Knapp GL, Kulig KW, et al. Efficacy of oral
N-acetylcysteine in the treatment of acetaminophen overdose.
Analysis of the national multicenter study (1976 to 1985). N Engl
J Med. 1988;319:1557-1562.
4. Rumack BH, Matthew H. Acetaminophen poisoning and toxicity.
Pediatrics. 1975;55:871-876.
5. Rumack BH. Acetaminophen hepatic toxicity: the first 35 years.
Clin Toxicol. 2002;40:3-20.
Clinical Policy on Pediatric Procedural Sedation
To the Editor:
I applaud Mace et al
for the ‘‘Clinical Policy: Evidence-
Based Approach to Pharmacologic Agents Used in Pediatric
Sedation and Analgesia in the Emergency Department,’’
published in the October 2004 issue of Annals. However,
in addition to identifying potential agents for emergency
department (ED) pediatric sedation, I believe it is equally
important to note those drugs that should not be considered
for this procedure. For example, chloral hydrate, diphenhydra-
mine, meperidine, and the ‘‘DPT cocktail’’ (demerol-phener-
gan-thorazine) have been used for decades for pediatric
sedation, despite their adverse risk profiles and absence of
supporting data.
Although many emergency physicians
choose better regimens (such as those described in the clinical
policy), these less-desirable agents of habit are still used in many
Figure 1. Rumack-Matthew nomogram. Modified from Rumack
BH, Peterson RC, Koch GC, et al. Acetaminophen overdose:
662 cases with oral acetylcysteine therapy. Arch Intern Med.
Figure 2. Sample calculation using Windows operating system
calculator (scientific view) for known ingestion with level drawn
at 7 hours and 20 minutes after acute ingestion.
564 Annals of Emergency Medicine Volume 45, no. 5 : May 2005
... Intoxicated patients are usually transported to toxicology centers, where they receive Nacetylcysteine (NAC) to prevent liver injury. This treatment is administered based on the Rumack-Matthew nomogram [5,6], which plots plasma paracetamol levels against the time since ingestion. Despite a widely available antidote therapy (NAC) and recognition of numerous risk factors, which have been discussed in the literature [7][8][9][10], acetaminopheninduced hepatotoxicity still occurs. ...
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Background and Objectives: Over-the-counter availability and a good safety profile make paracetamol one of the most common analgesics in developed countries but also the leading cause of liver failure due to overdose. The objectives of the study were to identify modifiable risk factors for severe hepatotoxicity following paracetamol overdose in adults. Materials and Methods: A retrospective cohort study involved the consecutive adult patients hospitalized in a toxicological center over a period of seven years due to paracetamol overdose. Complete medical datasets of laboratory and anamnestic variables were analyzed and validated by means of logistic regression model. Results: A total of 185 patients entered the study, including 25 individuals who developed severe hepatotoxicity (plasma aminotransferases levels above 1000 UI/L) and 31 individuals with mild to moderate liver injury (plasma aminotransferases levels above upper normal range, but below 1000 UI/L). In the univariable analysis, significant hepatotoxicity risk factors were male gender, alcohol abuse, an ingested paracetamol dose, and a timespan from ingestion to hospital admission. The later one was the only significant risk factor in the multivariable model (adjusted odds ratio 1.08; 95%CI: 1.03–1.12). Conclusions: A delay in hospital admission, resulting in a delayed administration of disease-specific treatment outweighs any other known risk factors of paracetamol-induced hepatotoxicity.
... We analysed plasma paracetamol, coagulation factor II-VII-X, international normalised ratio and alanine transaminase (ALT) during admission. The nomogram cut-off lines defined by White and Rumack were used (13). The plasma paracetamol tests used at the centres had different detection thresholds as follows: Hvidovre 0. As most of the children were unattended when they ingested paracetamol, and a significant amount of time could have passed before the caregivers suspected the ingestion, the exact time of the suspected intake was often unknown. ...
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Introduction: The accepted treatment for patients with acetaminophen/paracetamol overdose includes risk assessment based on the Rumack-Matthew (R-M) nomogram. Inaccurate use of the nomogram may result in improper treatment. Clinicians were surveyed to determine their understanding and proper use of this risk assessment tool in practice. Methods: Differences between visual risk assessment using the same depiction of the R-M nomogram and calculated risk assessment were determined using an online calculator developed based on the Rumack equation. An online survey was administered in French between August 25, 2021 and November 25, 2021 as a Google Form with 14 questions (the paracetamol concentration and time post-ingestion were stated). A total of 147 respondents with an average age of 32 years (range 23-61) performed risk assessment (low/possible/probable/not assessable). The mean assessment accuracy was 66.2 ± 26.7% [12.3-99.3]. The sensitivity, specificity, positive predictive value, and negative predictive value were 93%, 55%, 71%, and 89%, respectively. A sub-cohort of n = 31 senior clinicians showed the same trends (91%, 52%, 69%, 84%). Results: Approximately 7% of patients who are at risk of hepatotoxicity based on the R-M nomogram would not be treated. In contrast, N-acetylcysteine was not recommended by the R-M nomogram but would be administered to approximately 50% of patients. A concern for the latter group is that anaphylactoid reactions occur in up to 25% of patients with low paracetamol concentrations. Conclusion: Some patients may be under-treated, resulting in possible hepatotoxicity, and many patients may be over-treated, resulting in a high percentage of anaphylaxis. Rather than relying on visual risk assessment, physicians should use an online calculator ( or consult with a toxicologist or poison center to substantially improve patient care following acetaminophen/paracetamol overdose.
Background Recent recognition of “massive” acetaminophen (APAP) overdoses has led to the question of whether standard dosing of N-acetylcysteine (NAC) is adequate to prevent hepatoxicity in these patients. The primary aim of this study was to evaluate the clinical outcome for patients with massive APAP overdose who received standard intravenous NAC dosing of 300 mg/kg over 21 h. Methods This was a single-center retrospective cohort study conducted by chart review of APAP overdoses reported to a regional poison center from 1 January 2010 to 31 December 2019. Massive APAP overdose was defined by single, acute overdose resulting in an APAP concentration exceeding 300 mcg/mL at 4 h post-ingestion. Standard univariate statistical analysis was conducted to describe the cohort, and a multivariate logistic model was utilized to calculate adjusted odds ratios for risk of hepatoxicity. Results 1425 cases of APAP overdose were reviewed. 104 cases met the inclusion criteria of massive APAP overdose. Overall, 79 cases (76%) had no acute liver injury or hepatotoxicity, and 25 (24%) developed hepatoxicity. Nine percent (n = 4) of cases receiving NAC within 8 h developed hepatotoxicity. Crude odds for hepatoxicity was 5.5-fold higher for cases who received NAC after 8 h. Conclusions Standard NAC dosing received within 8 h prevented hepatoxicity in 91% (n = 40) of cases in our series of massive APAP overdoses. Additional data is needed to determine the clinical outcomes of massive APAP overdose using current intravenous NAC dosing.
While many drugs have some effect on serotonergic receptors this chapter focuses upon the toxicity seen with medications whose primary antidepressant therapeutic mechanism of action is to modify serotoninergic transmission. This includes selective serotonin reuptake inhibitors (SSRI), serotonin noradrenergic reuptake inhibitors (SNRI), and tetracyclic and triazolopyridine antidepressants (Tables 1, 2, 3, and 4).
While many drugs have some effect on serotonergic receptors this chapter focuses upon the toxicity seen with medications whose primary antidepressant therapeutic mechanism of action is to modify serotoninergic transmission. This includes selective serotonin reuptake inhibitors (SSRI), serotonin noradrenergic reuptake inhibitors (SNRI), and tetracyclic and triazolopyridine antidepressants (Tables 1, 2, 3, and 4).
Patients with acute poisonings are frequently seen in the Emergency Department. The objectives of this study were to measure the quality of care offered to intoxicated patients, to identify those aspects that did meet quality standards, to apply corrective measures in the processes where improvement was possible and to monitor the results obtained. In the first stage, a map of 27 quality indicators was drawn up. Five were structural, 17 procedural, 2 result-based, 2 administrative and 1 of perceived quality. During the month of October 2004, information on the care of intoxicated patients was reviewed, the results, in terms of indicators, were noted and it was determined whether the care process met the pre-established quality standard. In the second stage, a guide to good practice in the care of intoxicated patients was drawn up and distributed to physicians working in the Emergency Department. In addition, training sessions for the nursing staff were organized. In the third stage (October 2005) information on the care of patients was reviewed again using the same methodology. The results obtained in 2005 show that one of the procedural indicators (recording of vital signs) improved (p<0,001) and two (delay in receiving medical care [p=0,015] and delay in carrying out gut decontamination [p=0,030]) worsened compared with 2004. In the remaining indicators, no significant differences were found, although 59% were below the quality standard established. The quality of care offered to intoxicated patients in the Emergency Department is measurable and comparable over time using indicators. The strategy used to improve the results obtained using quality indicators was not very effective and should be improved in the future.
We present a map of 24 indicators to measure the quality of care given to patients with acute poisoning attended in the emergency department. These include structural indicators (availability of protocols, stocks of antidotes, analytical tests, gastric lavage tubes), process indicators (correct indication of gut decontamination techniques, indications for renal and extra-renal purification, use of antidotes, indication of toxicological analyses, ECG, delays in care, psychiatric referrals, judicial notifications), indicators of results (mortality, compliance with minimum basic data set of poisonings, continuing staff education) and administrative indicators (publications).
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Acetaminophen (paracetamol in British literature) is a metabolite of phenacetin which has become increasingly popular as a substitute for salicylates.1 The popularity of acetaminophen has been encouraged by the medical profession because it is allegedly safer than aspirin.2 However, experience in Britain indicates that acute acetaminophen overdosage is both common and significantly more toxic than of salicylates.3-7 Although it is widely used in the United States, only one report describing a single American patient has appeared in the literature.8 This is a puzzling situation. It is axiomatic that if you do not look for something you will not diagnose it. This may provide the answer as there is apparently a general lack of knowledge in the United States concerning the toxicity of acetaminophen. Indeed, one of us (B.H.R.) contacted nine American University poison services in the spring of 1973 and discovered that none had clinical experience or analytical methods in operation. During the past year, however, with a high index of suspicion in Denver, 156 ingestions with four fatalities have been recorded. Because of the nonspecific initial features of acute overdosage, the lack of coma, the delay in onset of jaundice and the rapid fall in detectable plasma levels of acetaminophen, the cause-and-effect relationship may be missed in even a floridly ill or dying patient. Hepatoxicity is the most remarkable feature and the question must be raised as to how many cases of "jaundice of unknown etiology" are actually due to this drug. This review is intended to provide an understanding of the current knowledge of this drug. It should be noted that although toxicity and fatalities have occurred in the adolescent age group, only one death in younger children has been recorded.
Full-text available
During the investigational use of oral N-acetylcysteine as an antidote for poisoning with acetaminophen, 11,195 cases of suspected acetaminophen overdose were reported. We describe the outcomes of 2540 patients with acetaminophen ingestions treated with a loading dose of 140 mg of oral N-acetylcysteine per kilogram of body weight, followed four hours later by 70 mg per kilogram given every four hours for an additional 17 doses. Patients were categorized for analysis on the basis of initial plasma acetaminophen concentrations and the interval between ingestion and treatment. Hepatotoxicity developed in 6.1 percent of patients at probable risk when N-acetylcysteine was started within 10 hours of acetaminophen ingestion and in 26.4 percent of such patients when therapy was begun 10 to 24 hours after ingestion. Among patients at high risk who were treated 16 to 24 hours after an acetaminophen overdose, hepatotoxicity developed in 41 percent--a rate lower than that among historical controls. When given within eight hours of acetaminophen ingestion, N-acetylcysteine was protective regardless of the initial plasma acetaminophen concentration. There was no difference in outcome whether N-acetylcysteine was started zero to four or four to eight hours after ingestion, but efficacy decreased with further delay. There were 11 deaths among the 2540 patients (0.43 percent); in the nine fatal cases in which aminotransferase was measured before treatment, values were elevated before N-acetylcysteine was started. No deaths were clearly caused by acetaminophen among patients in whom N-acetylcysteine therapy was begun within 16 hours. We conclude that N-acetylcysteine treatment should be started within eight hours of an acetaminophen overdose, but that treatment is still indicated at least as late as 24 hours after ingestion. On the basis of available data, the 72-hour regimen of oral N-acetylcysteine is as effective as the 20-hour intravenous regimen described previously, and it may be superior when treatment is delayed.
Full-text available
Six hundred sixty-two consecutive patients with acetaminophen overdoses were evaluated. Those at risk on the basis of their acetaminophen blood levels, as plotted on the study nomogram, were treated with oral acetylcysteine. Statistically significant differences in severity of hepatic toxicity were observed between patients treated within 16 hours after ingestion and those treated between 16 and 24 hours after ingestion. No deaths occurred among patients treated within 24 hours of ingestion, except for one patient who was an alleged gunshot homicide. Seven percent of patients with plasma acetaminophen levels in the potentially toxic range and treated with acetylcysteine within ten hours of ingestion showed transient SGOT level elevations, whereas 29% of those treated between ten and 16 hours after ingestion and 62% of those treated between 16 and 24 hours after ingestion showed such transient toxicity. No consistent difference in hepatotoxicity could be demonstrated between those patients with a history of chronic alcohol use and those patients with no history of chronic alcohol use. Acute alcohol use resulted in less severe toxic reactions than in those patients without acute alcohol use.
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The acetaminophen nomogram including its uses and limitations is discussed as well as the development of the N-acetylcysteine protocol. While it has taken many years to elucidate the genetic variability and true multiplicity of the cytochrome P450 "mixed function oxidase system" many publications early on looked at the enzyme system as a single entity. Numerous articles indicated that barbiturates, anticonvulsants, and others could induce "P450" and add to the toxicity of acetaminophen. It rapidly became apparent that just because "P450" was induced when measured as a whole, not all other substrates would have changed metabolic activity. The role of diet and ethanol induction and inhibition on CYP2E1, the enzyme of greatest interest for acetaminophen is multifaceted. The lack of enhancement of acetaminophen toxicity by phenytoin and in fact, the potential for reduction of toxicity with that agent is a good example of the evolution of our knowledge. Further complicating our understanding is the introduction of misleading terms such as "therapeutic misadventure" and other expressions of molecular intent. A critical understanding of the literature makes it clear that therapeutic doses of acetaminophen either alone or in the presence of inducers do not produce toxicity. While the community of clinical toxicologists is small, it needs to be more aggressive in making sure that physicians from other specialties and non-clinical toxicology colleagues understand the significance and implications of this science.
AAPCC's 2003 fatality verification process involved the preparation and review of abstracts on 1,390 fatalities reported to poison centers, some of which were eventually determined to be unrelated to a poison exposure.
Acetaminophen overdose: 662 cases with oral acetylcysteine therapy
  • Bh Rumack
  • Rc Peterson
  • Koch
  • Gc
Rumack BH, Peterson RC, Koch GC, et al. Acetaminophen overdose: 662 cases with oral acetylcysteine therapy. Arch Intern Med. 1981; 141:380-385.
Acetaminophen overdose: 662 cases with oral acetylcysteine therapy
  • Rumack