Cohort
Suzanne Doyon, MD and Wendy Klein-Schwartz, PharmD, MPHHepatotoxicity Despite Early Administration of Intravenous N-Acetylcysteine for Acute Acetaminophen Overdose
ACADEMIC EMERGENCY MEDICINE
2009; 16:34–39
- Submitted by:Jason Hamel - Medical Student
- Institution:Loma LInda University School of Medicine
- Date submitted:28th October 2009
1
Objectives and hypotheses
1.1
Are the objectives of the study clearly stated?
Yes: "evaluate the effectiveness of intravenous N-acetylcysteine (IV NAC; 300 mg/kg over 21 hours) in early acute acetaminophen overdose patients."
2
Design
2.1
Is the study design suitable for the objectives?
Yes, the retrospective cohort allowed the observation of treatment outcome for patients given N-acetyl cysteine after acetaminophen overdose.
2.2
Who / what was studied?
Hepatotoxicity in patients with known acetaminophen overdose who subsequently received N-acetyl cysteine.
2.3
Was a control group used if appropriate?
No, this was an observational case series
2.4
Were outcomes defined at the start of the study?
Yes, Hepatotoxicity was defined as hepatic aminotransferase levels greater than 1,000 IU ⁄ L.
2.5
Was this the right sample to answer the objectives?
Yes, the patient sample was appropriate considering the objectives
2.6
Is the study large enough to achieve its objectives? Have sample size estimates been performed?
No sample size estimates were mentioned in the study
2.7
Were all subjects accounted for?
Yes, data was gathered on 119 patients, 42 met exclusion criteria, 77 met inclusion criteria
2.8
Were all appropriate outcomes considered?
Yes, hepatotoxicity as well as mortality was documented. Hepatotoxicity was
defined as hepatic aminotransferase levels greater than 1,000 IU ⁄ L.
defined as hepatic aminotransferase levels greater than 1,000 IU ⁄ L.
2.9
Has ethical approval been obtained if appropriate?
Yes, the study was deemed exempt from informed consent by the University of Maryland Baltimore Investigational Review Board.
3
Measurement and observation
3.1
Is it clear what was measured, how it was measured and what the outcomes were?
Yes, data collected were APAP formulation, time of ingestion, method of gastrointestinal decontamination, initial and end-of-21-hour IV NAC plasma APAP concentration, time of ingestion, time to initiation of IV NAC, dose and infusion rate of IV NAC, initial and end-of-21-hour IV NAC AST and ALT, and international normalized ratio (INR).
3.2
Was the assessment of outcomes blinded?
No, reviewers were nonblinded
3.3
Was follow up sufficiently long and complete?
Given that this was a retrospective study, follow-up was as long as needed to meet inclusion criteria, one patient was excluded for not completing the 21 hour N-acetylcysteine treatment. Two patients were lost to follow-up
3.4
Are the measurements valid?
Yes. Seven patients received antidotal therapy for greater than 21 hours. These patients tended to have ingested combination preparations, have very high initial plasma APAP concentrations, and had persistently elevated plasma concentrations during their hospital stay. Detailed clinical and laboratory data on these seven patients are provided in Table 2.
3.5
Are the measurements reliable?
Yes. reporting to poison centers is voluntary, so there is a possible reporting or selection bias.
3.6
Are the measurements reproducible?
Yes
4
Presentation of results
4.1
Are the basic data adequately described?
Yes, tables 1 and 2 provide an adequate representation of the basic data.
4.2
Are the results presented clearly, objectively and in sufficient detail to enable readers to make their own judgement?
Yes
4.3
How large are the effects within a specified time?
Hepatotoxicity occurred in 5.2% (95% confidence interval = 0.2% to 10.1%) of the patients receiving at least the standard 21 hour N-acetylcysteine treatment
4.4
Are the results internally consistent, i.e. do the numbers add up properly?
Yes, of the 77 total patients 4 were said to have suffered hepatotoxicity while 73 did not.
5
Analysis
5.1
Are the data suitable for analysis?
Yes, data were analyzed for patient demographics (age, gender); estimated dose and time of ingestion; plasma
APAP concentration; liver function tests; management (e.g., activated charcoal), exact dosing, and length of
infusion of IV NAC; and medical outcome.
APAP concentration; liver function tests; management (e.g., activated charcoal), exact dosing, and length of
infusion of IV NAC; and medical outcome.
5.2
Are the methods appropriate to the data?
Yes
5.3
Are any statistics correctly performed and interpreted?
Yes, Fisher’s exact test and Wilcoxon rank sum test were used to compare parameters such as age, plasma APAP concentrations, time to maximum plasma APAP concentration, time of initiation of therapy, and type of product between patients who received 21 hours of IV NAC only and patients who received prolonged IV NAC therapy (> 21 hours).
6
Discussion
6.1
Are the results discussed in relation to existing knowledge on the subject and study objectives?
Yes, Table 3 shows a comparison of selected studies evaluating NAC in early presenting acute APAP overdoses with plasma concentrations on or above the 200 mg/L line on the Rumack-Matthew Nomogram.
6.2
Is the discussion biased?
No
7
Interpretation
7.1
Are the author's conclusions justified by the data?
Yes, the data showed that hepatotoxicity developed in 5.2% of APAP overdose patients recieving the standared 21-hour NAC treatment. The authors concluded that this suggests that this treatment regimen is suboptimal under certain circumstances.
7.2
What level of evidence has this paper presented? (using CEBM levels)
2b
7.3
Does this paper help me to answer my problem?
This paper does more to define the need for further studies than it does to impact clinical decision making.
8
Implementation
8.1
Can any necessary change be implemented in practice?
Not without further studies, the level of evidence is lacking.
8.2
What aids to implementation exist?
The authors propose a tailored approach to the discontinuation of IV NAC based on the following laboratory parameters at 21 hours: undetectable plasma APAP concentration and normal AST and ALT. Further study
is needed to determine the optimal IV NAC regimen, including dose and duration of infusion, in patients
who fail to meet these laboratory parameters at 21 hours.
is needed to determine the optimal IV NAC regimen, including dose and duration of infusion, in patients
who fail to meet these laboratory parameters at 21 hours.
8.3
What barriers to implementation exist?
Although IV NAC has been used for 30 years worldwide, data are lacking regarding its effectiveness in
early-presenting APAP overdose patients.
early-presenting APAP overdose patients.
8.4
Are the study patients similar to your own?
Yes, the patient demographics were balanced
8.5
Does the paper give any conclusions that will affect what you will offer or tell your patient?
No, though patients can be told that there is some evidence that 21-hour regimen of IV NAC for acetaminophen overdose does not prevent progression to hepatotoxicity in some patients.