TABLE 5.
| Heterogeneity and quality assessment of 13 prospective studies included in the analysis.
| Author (year) | Study design/patient number | Results | Comments/limitations |
|---|---|---|---|
| Smilkstein et al. (1988) | Multileft involving 2540 | The 72-h regimen of oral NAC was as effective as the 20-h I.V. regimen and may be superior when treatment was delayed | There may be a selection bias in the choice of patient-associated factors, which may increase or diminish the potential for hepatotoxicity (e.g., ethanol or other drugs were not analyzed) |
| patients | |||
| Rigges et al. (1989) | Prospective cohort study involving 60 patients | There was a statistically significant correlation between the time to a loading dose of NAC and pregnancy outcomes, with an increase in the incidence of spontaneous abortion or fetal death when treatment began late. Pregnant women who take an acetaminophen overdose and have a potentially toxic serum level should be treated with NAC as early as possible | This is the only study involving pregnant women |
| Smilkstein et al. (1991) | Nonrandomized trial involving 179 patients | 48-h I.V. NAC protocol is equal to 72-h oral and 20-h I.V. treatment protocols when started early and superior to the 20-h I.V. regimen when treatment is delayed. NAC-induced adverse effects were dose-related | There was no randomization of treatment |
| Analysis of other factors theorized to affect acetaminophen toxicity was limited (ethanol use, other drugs, nutritional status) | |||
| Perry and Shannon (1998) | Prospective with historical controls of 54 patients | This study considered pediatric patients | |
| Route of administration was discretionary | |||
| Schmidt et al. (2002) | Prospective study involving 645 patients | Time to NAC was the major risk factor in acetaminophen-induced hepatotoxicity and mortality. Chronic alcohol abuse was an independent risk factor, which could be counteracted by concomitant acute alcohol ingestion | Partly retrospective design |
| Betten et al. (2007) | Prospective observational, 205 patients | A shortened duration of NAC treatment (20–48 h) may be an effective option in individuals considered to be at no further risk of developing liver toxicity according to laboratory criteria (serum APAP undetectable and liver test results normal) before NAC discontinuation | Limited sample size of patients |
| Some patients were unable to be contacted after discharge | |||
| Waring et al. (2008) | Prospective, 362 patients | High serum acetaminophen concentrations were associated with fewer anaphylactic reactions, suggesting that these might in some way be protective | Study design did not address the biological bases for an association between acetaminophen concentrations and anaphylactic reactions |
| Doyon and Klein-Schwartz (2009) | Prospective, cohort, 77 patients | Hepatotoxicity developed in 5.2% of cases, suggesting that the 21-h I.V. NAC regimen is suboptimal in some patients. In addition to high initial plasma APAP concentrations, APAP product formulation and persistently elevated plasma APAP concentrations were identified as factors possibly associated with developing hepatotoxicity | Retrospective study |
| Small number of patients | |||
| Reporting to the poisoning was voluntary, with possible bias | |||
| Reviewers were not blinded | |||
| Horowitz et al. (1997) | Case series involving 4 patients | This study considered pregnant women and their infants discharged without liver injury | Pregnant and placental transfer of NAC |
| NAC was detected in the blood of infants and there was no evidence of APAP-related toxicity | |||
| Heard et al. (2014) | Multileft, single-arm, open-label clinical trial, involving 309 patients | APAP-overdosed patients treated with I.V. acetylcysteine administered as a 140 mg/kg loading dose, followed by 70 mg/kg every 4 h for 12 doses, had a low rate of hepatotoxicity and few adverse events | The study design did not have a comparator group. There is a long interval between data collection and publication |
| Gheshlaghi (2006) | Case series anterograde and descriptive analytic study, involving 173 patients | Different atopic diseases must be considered a risk factor in the development of side effects to I.V. NAC therapy | It is not a case-controlled study |
| Larson et al. (2005) | Prospective study, involving 275 patients | Detailed prospective data were gathered on 662 consecutive patients fulfilling standard criteria for ALF (coagulopathy and encephalopathy), from which 275 (42%) were determined to result from APAP liver injury. Unintentional overdoses accounted for 131 (48%) cases, intentional 122 (44%), and 22 (8%) were of unknown intent. Transplant-free survival rate and rate of liver transplantation were similar between intentional and unintentional groups | APAP hepatotoxicity far exceeds other causes of acute liver failure in the United States. Susceptible patients have concomitant depression, chronic pain, and alcohol or narcotic use, and/or take several preparations simultaneously |
| Rumack (1984) | Multileft, open, prospective study, involving 417 children | Even though APAP has been frequently ingested, it infrequently has serious consequences. Alcohol seems to have some degree of hepatoprotection when ingested simultaneously. Miscellaneous additional ingestants increase the risk of lethargy and result in a higher transient elevation of AST level | The purpose of this study was to evaluate the nature of toxic reactions to a substantial overdose of acetaminophen in children aged 5 years or younger |