paracetamol overdose remains one of the most important common poisonings in many parts of the world and an increasing problem in many developing and resource poor nations .
n - acetylcysteine ( nac ) is an effective treatment in the vast majority of cases if given early .
the decision to give nac is usually based on a paracetamol concentration measured at least 4 h after ingestion or later if the patient presents to hospital after this time .
although dose is recognised as a predictor of toxicity , reported dose is rarely used to define treatment if a paracetamol concentration is available . 
 
it remains unclear what the toxic dose of paracetamol is and in the majority of cases patients will have a serum paracetamol concentration measured irrespective of the reported dose taken .
australian and most international guidelines recommend 200 mg / kg or 10 g as a toxic dose .
however , despite this being defined as a toxic dose the majority of patients will have a serum paracetamol concentration measured , even if they have ingested less than this amount
. a comparison of the reported and toxic dose is only used in cases where a serum paracetamol concentration is not available ( i.e. late presentations ) or in resource poor settings where laboratory services are not available .
although previous studies have shown that reported dose is an independent predictor of hepatotoxicity , this has not influenced risk assessment in paracetamol poisoning . 
 
if reported dose was a strong predictor of hepatotoxicity , then its use would potentially allow early initiation of nac in large overdoses or conversely avoid waiting for paracetamol concentrations for non - toxic doses .
this is already done in some cases with massive ingestions , but this is based on anecdotal evidence .
currently , the practice of a single serum paracetamol concentration being above the nomogram between 4 and 24 h from ingestion remains the gold standard for starting nac therapy .
starting nac prior to measuring a paracetamol concentration has been suggested as a potential approach in paracetamol poisoning because it allows for slower administration rates , that is the loading dose to be given over a longer duration .
however , it would be best if nac was only given to patients with a high probability of requiring nac .
therefore , predicting whether the paracetamol concentration will be above the nomogram line based on reported dose is of significance .
the primary aim of this study was to determine whether reported paracetamol dose was predictive of the need for nac .
in addition , we will investigate whether a minimal dose could be defined below which treatment may not be required ( e.g. < 10% ) and a maximum dose above which the probability of requiring nac was greater than 90% .
this study included dosing and drug concentration data from single acute paracetamol overdoses recorded in a prospective database .
the use of the database and de - identified patient information has been granted exemption as an audit by the local human research ethics committee .
information for all presentations to a large regional toxicology centre was collected prospectively using a standardised data collection form that is completed at the time of presentation by the treating doctor .
this information and any additional data from the medical record were entered into a relational database by trained research assistants .
this included demographic information , details of the overdose / exposure ( time of overdose and reported dose ingested ) , clinical information , laboratory investigations and treatment .
all paracetamol overdoses ( single acute ingestions > 1 g ) presenting to the toxicology service between january 1997 and december 2011 were extracted from the database .
cases were only included if there was a serum paracetamol concentration measured between 4 and 16 h after ingestion , and both the time of ingestion and the amount ingested were reported and recorded in the database .
we used reported dose to represent the dose that the treating clinicians believe the patient took .
the reported dose was based on the patient history which was confirmed on multiple occasions and cross checked with any collateral history from the family , friends or pre - hospital services ( e.g. ambulance ) .
note the actual dose remains unknown and the perceived discrepancy between actual and reported dose is often perceived as the basis for uncertainty in the decision about treatment .
the following data were extracted from the database : age , sex , reported dose ingested , time of ingestion , paracetamol concentration and the time of the paracetamol concentration ( between 4 and 16 h ) , peak alanine transaminase ( alt ) and treatment ( single dose activated - charcoal [ sdac ] and nac ) .
patients were further divided into two groups based on the time of their first paracetamol concentration .
early presenters were defined a priori as those that had their first paracetamol concentration between 4 and 7 h and could have nac started within 8 h. late presenters were defined as those that had their first level between 7 and 16 h post - overdose and were commenced on nac on admission .
seven hours was chosen as the cut - off because this meant that nac could be commenced within 8 h. hepatotoxicity was defined as an alt > 1000 u / l . for ease of interpretation
data extracted from the database were analysed within a repeated measures logistic regression framework using nonmem ( ver 7.2 ) .
the data were presented as 0 if the serum paracetamol concentration was below the line of the nomogram and hence no dose of nac would usually be given and 1 if the concentration was above the nomogram .
the nomogram used started from 150 mg / l ( 1000 m ) at 4 h and decreased with a half - life of 4 h. factors that were considered were age , sex , reported paracetamol dose and sdac .
model building was based on the likelihood ratio test where a decrease in the difference of two objective functions ( proportional to twice the negative log - likehood ) were assumed to be chi - squared distributed with the degrees of freedom equivalent to the difference in the number of parameter values for nested models .
the general form of the linear model was : with additional terms being added for other effects ( e.g. sdac ) as required . following transformation , the probability that nac would be administered : the probability that the serum paracetamol concentration is greater than the value on the nomogram was the primary measure in the study but is considered to be a surrogate marker of the probability that nac would have been administered .
for ease of interpretation continuous variables are presented as medians with interquartile ranges ( iqr ) .
data extracted from the database were analysed within a repeated measures logistic regression framework using nonmem ( ver 7.2 ) .
the data were presented as 0 if the serum paracetamol concentration was below the line of the nomogram and hence no dose of nac would usually be given and 1 if the concentration was above the nomogram .
the nomogram used started from 150 mg / l ( 1000 m ) at 4 h and decreased with a half - life of 4 h. factors that were considered were age , sex , reported paracetamol dose and sdac .
model building was based on the likelihood ratio test where a decrease in the difference of two objective functions ( proportional to twice the negative log - likehood ) were assumed to be chi - squared distributed with the degrees of freedom equivalent to the difference in the number of parameter values for nested models .
the general form of the linear model was : with additional terms being added for other effects ( e.g. sdac ) as required .
following transformation , the probability that nac would be administered : the probability that the serum paracetamol concentration is greater than the value on the nomogram was the primary measure in the study but is considered to be a surrogate marker of the probability that nac would have been administered .
from a total of 2990 paracetamol poisoning admissions there were 1571 acute paracetamol overdoses with a reported dose , known time of ingestion and a paracetamol concentration performed between 4 and 16 h post - overdose .
the reasons for exclusion were no known time of ingestion ( 385 ) , no reported dose ( 94 ) , dose less than 1 g ( 26 ) and no paracetamol concentration between 4 and 16 ( 914 ) .
the 1571 admissions were in 1303 patients , 1173 patients presented on one occasion and 130 on two or more occasions .
the median age was 27 years ( range : 1296 years ; iqr : 2039 years ) and 1140 ( 72.6% ) were females .
the median dose ingested was 10 g ( range : 1100 g ; iqr : 616 g ) .
the paracetamol concentration was above the 150/1000 nomogram line in 337 of 1571 ( 21.5% ) and 300 of these received nac .
an additional 143 patients received nac who did not have a paracetamol concentration above the nomogram .
comparison of patients with an early ( 47 h ) first paracetamol concentration to patients with a late ( 716 h ) first paracetamol concentration .
table 1 compares patients who presented early ( had a serum paracetamol concentration taken between 4 and 7 h post - overdose ) , to those who presented late ( with a serum paracetamol concentration between 7 and 16 h ) .
patients who presented later had a higher rate of hepatotoxicity ( 5.5% vs. 0.4% ; p < 0.0001 ) , were more likely to have a paracetamol concentration above the nomogram ( 33.6% vs. 18.2% ; p < 0.0001 ) and more likely to receive nac ( 47.6% vs. 23.0% ; p < 0.0001 ) .
the final model included paracetamol reported dose , age , sex and use of sdac .
the data were not able to support a random effect on either the baseline or the influence of reported dose on the probability of the serum paracetamol concentration being above the nomogram line .
there was no interaction between the use of sdac and ingested dose , age or sex .
the probability of the paracetamol concentration being above the nomogram line based on the dose given is shown in fig . 1 for 30-year - old females and males
. the probability of being above the nomogram line was lower for males at a similar dose compared to that for females .
the influence of the ingested overdose dose on the adjusted probability of being above the nomogram line is given by the solid line .
the probability based on dose is adjusted for the influence of sdac ( dashed line ) , age of the patient and sex of the patient .
it is seen that sdac reduces the probability of being above the nomogram line , shown by the dashed lines in fig .
1 . sdac reduces the probability of nac by up to 14% at 28 g and less than 10% at either doses lower than 19 g or doses greater than 37 g. probability of the paracetamol concentration being above the nomogram line versus dose ( a ) for a 30-year - old female with ( dashed line ) and without ( solid line ) sdac ; and ( b ) for a 30-year- old male ( solid line ) compared to a 30-year - old female ( dashed line ) .
based on sdac not being administered then there was a 5% probability of being above the nomogram line at a dose of 69 g , a 10% probability of being above the nomogram line at a dose of 1316 g , a 50% probability of being above the nomogram line at a dose of 3034 g and a 90% probability of being above the nomogram line at 4850 g.
this study demonstrates that reported dose is a strong predictor of patients having paracetamol concentrations above the nomogram line .
it has also shown that patient age , sex and the administration of sdac influences this probability . the relationship between reported dose and toxic paracetamol concentration can potentially be used to allow early intervention in large overdoses .
the study also confirmed that patients presenting 7 h or more after ingestion , who were therefore not administered nac within 8 h , were more likely to receive nac and develop an abnormal alanine transaminase .
this supports current practice of commencing nac prior to getting a paracetamol concentration in all patients presenting after 8 h and then ceasing it if the paracetamol concentration is below the nomogram line .
most guidelines recommend that patients presenting within 8 h have a serum paracetamol concentration measured prior to commencing nac   wait and see approach  .
the results of this study suggest that if the reported dose is greater than 50 g then more than 90% of patients require treatment so nac could potentially be commenced earlier in these patients .
an alternate approach has been to commence nac early and stop it if the paracetamol concentration is non - toxic . for this approach ,
reported doses associated with a low probability of requiring nac could be used to define a group of patients where nac should not be commenced prior to a paracetamol concentration being determined . in other words , a reported dose cut - off
could be used to determine patients where a  wait and see approach  is followed ( < cut - off dose ) or an approach to commence nac prior to obtaining a paracetamol concentration ( > cut - off dose ) and then revisit the use of nac once a paracetamol concentration is available .
for instance , if a reported dose of 10 g was used this would prevent half of all paracetamol overdose patients ( in this study ) being started on nac early ( i.e. if all patients are initially commenced on nac prior to a paracetamol concentration ) , with the associated small risk of adverse reactions .
patients ingesting 10 g only have a 57% probability of being above the nomogram line and therefore requiring nac .
this study confirms a previous study ( data prior to 1997 ) at the same toxicology unit which demonstrated that the administration of sdac reduces the probability of requiring nac .
this would support the early administration of activated charcoal in cooperative patients to reduce the number of patients requiring nac and therefore reduce the length of stay .
the study suggests that there is the greatest benefit of sdac for doses greater than 28 g. however , although sdac is a low risk intervention it could not be given as a duty of care in these patients because nac is an effective antidote .
there are a number of limitations to the study including the retrospective extraction and review of the data . however , this is unlikely to affect the primary aim of the study which was based on the reported dose and the measured serum paracetamol concentration .
previous studies have demonstrated that reported dose is a good estimate of the true ingested dose and that patient history is reliable in the majority of cases although this remains a point of controversy in the literature .
another problem was that a large number of patients ( 47% ) were excluded which may introduce selection bias .
however , the majority ( 31% ) were because a paracetamol concentration was not done between 4 and 16 h and includes late presenters , staggered , supratherapeutic and chronic paracetamol ingestions , where risk assessment is generally not based on a single paracetamol concentration plotted on the nomogram .
another limitation was that sdac was administered according to the emergency department doctor or treating clinical toxicologist and was not randomised .
this may have meant that patients ingesting larger doses were more likely to receive sdac .
however , there was no interaction between dose and sdac in the logistic regression model suggesting that this was unlikely to be the case .
there were a number of patients with paracetamol concentrations above the nomogram who did not receive nac .
this is most likely to be patients between the 150 and 200 mg / l nomogram lines who were not treated since this was prior to the change in australia from the 200 mg / l nomogram line to the 150 mg / l nomogram line .
in addition to dose and sdac , the final logistic regression model included both age and sex as significant covariates .
figure 1 shows that there was a greater probability of the serum paracetamol being above the line in females compared to males .
this may be because females on average weigh less than males and weight was not included in the model because it was not available in the majority of patients .
the study shows that reported dose can be used as an early predictor of patients who require nac .
this may improve the risk assessment in patients with paracetamol poisoning allowing the earlier administration in large overdoses or more targeted use of nac in early and late presenters .
 context there is contention over whether reported dose correlates with toxicity in paracetamol poisoning and risk assessment is currently based on serum paracetamol concentration compared to a nomogram , irrespective of reported dose.objectiveto determine if reported dose predicts the need for n - acetylcysteine ( nac).methodsdata were taken from paracetamol overdoses presenting to a tertiary toxicology service . 
 age , sex , reported dose , ingestion time , timed paracetamol concentrations between 4 and 16 h , hepatotoxicity ( peak alanine transaminase > 1000 
 u / l ) and treatment ( single dose - activated charcoal [ sdac ] and nac ) were analysed . 
 data were analysed within a repeated measures logistic regression framework using nonmem ( ver 7.2 ) . 
 the primary outcome was administration of nac , which was determined based on a serum paracetamol concentration greater than the nomogram line.resultthere were 1571 admissions in 1303 patients , with a median age of 27 years ( 1296 years ) and 1140 ( 73% ) were females . 
 the median dose was 10 g ( 1100 g ) . 
 the paracetamol concentration was above the nomogram line in 337 of 1571 ( 22% ) patients . 
 patients presenting later ( first paracetamol concentration between 7 and 16 h post - overdose ) compared to those presenting earlier ( 47 h post - overdose ) were more likely to have hepatotoxicity ( 5.5% vs. 0.4% ; p < 0.0001 ) , have a toxic paracetamol concentration ( 34% vs. 18% ; p < 0.0001 ) and receive nac ( 48% vs. 23% ; p < 0.0001 ) . 
 sdac reduced the probability of the paracetamol concentration being above the nomogram . 
 based on sdac not being administered there was a 5% probability of requiring nac at a dose of 69 g , a 10% chance of requiring nac at a dose of 1316 g , a 50% chance of requiring nac at a dose of 3034 g and a 90% chance for needing nac at 4850 g.conclusionreported dose was a good predictor of a toxic paracetamol concentration and sdac reduced the probability of the concentration being above the nomogram . 
 these predictions may assist in determining which patients could be started on nac immediately . 