TABLE 4.
| Heterogeneity and quality assessment of 18 retrospective studies included in the analysis.
| Author (Year) | Study design/patient number | Results | Comments/limitations |
|---|---|---|---|
| Prescott et al. (1979) | Retrospective study involving 100 patients | Efficacy of NAC diminished progressively and treatment after 15 h was completely ineffective | This was one of the first studies on NAC for paracetamol poisoning, and this study described the results of only 100 cases |
| Compared to cysteine and methionine, NAC was more effective and safer | |||
| Harrison et al. (1990) | Retrospective study involving 43 patients | This study considered fulminant hepatitis and good outcome after late administration of NAC | Results needed to be confirmed in a prospective, randomized, placebo-controlled trial |
| Yip et al. (1998) | Retrospective consecutive case series involving 1131 patients | I.V. administration of the oral NAC preparation appears to have limited adverse effects and offers another mechanism of delivery of the potentially lifesaving NAC when oral administration is not possible | Retrospective nature of the study |
| Human error during processing data | |||
| Buckley et al. (1999) | Case series involving 205 patients | A shorter hospital stay, patient and doctor convenience, and the concerns over the reduction in the bioavailability of oral NAC by charcoal and vomiting make I.V. NAC preferable for most patients with acetaminophen poisoning | |
| McCormick et al. (2000) | Not reported involving 110 patients | Delays in treatment of APAP overdose are common and may be clinically important in the small minority of patients with significant liver injury; it is possible that oral administration of NAC (that can be given immediately) may reduce these delays | The design of the study did not allow the determination of the cause of the delays in the administration of NAC |
| Only one of the two hospitals chosen had APAP level testing | |||
| Woo et al. (2000) | Retrospective cohort study involving 75 patients | Patients without evidence of hepatotoxicity within 36 h of an acute overdose can be safely and effectively treated with a shorter course of oral NAC therapy (24 h or less) | Retrospective study |
| Small number of patients | |||
| Whyte et al. (2007) | Retrospective analysis involving 399 patients | Hepatotoxicity was significantly less likely when I.V. NAC was administered within 8 h after APAP ingestion compared with longer intervals | This study could not exclude certain sources of biases, including temporal changes over the 16-year course of data collection in the use of I.V. NAC and low ascertainment of mild, self-limiting reactions to I.V. NAC |
| Myers et al. (2008) | Retrospective, 290 patients | APAP overdose had a relatively benign short-term course but was associated with substantial long-term mortality caused by preventable conditions, such as unintentional overdoses, alcohol abuse, and underlying liver disease | Low accuracy of administrative data for APAP overdose, overdose intent, liver disease, and alcohol abuse |
| Lack of external validation | |||
| Data only in hospitalized patients | |||
| Yarema et al. (2009) | Retrospective with historical controls | The risk of hepatotoxicity differed between the 20-h and 72-h protocols according to the time to initiation of acetylcysteine. It favored the 20-h protocol for patients presenting early and favored the 72-h protocol for patients presenting late after acute acetaminophen overdose | Comparison of retrospective vs. prospective |
| 4048 patients (2086 I.V.–1962 os) | Confounding: pre-existing liver disease | ||
| Alhelail et al. (2011) | Retrospective, 119 patients | Patients with repeated supratherapeutic ingestion of APAP who developed hepatotoxicity presented with abnormal ALT levels. A history of alcoholism and an elevated creatinine level at presentation are markers of increased risk for hepatotoxicity and death | Retrospective study |
| Considered only variable included in the original medical record | |||
| Lack of comments on course of untreated patients | |||
| Khandelwal et al. (2011) | Retrospective, 210 patients | This study confirms and extends previous observations regarding the high (18%) prevalence of unrecognized or uncertain acetaminophen toxicity among subjects with indeterminate acute liver failure. NAC use was limited presumably because of the lack of a specific diagnosis of APAP toxicity. | Retrospective reports |
| Offerman (2011) | Retrospective cohort, 428 patients | Use of I.V. NAC did not impact hospital length of stay | Data on the exact time of ingestion and the reported dose of APAP ingested were not collected |
| Pettie et al. (2012) | Retrospective, case note review, 71 patients | Implementation of an integrated care pathway (ICP) for APAP poisoning significantly improved patient management and helped to standardize interprofessional decision-making in this challenging patient group, improving patient outcomes | Results of the study are based on the introduction of the ICP within a specialist unit. |
| Retrospective reports | |||
| Cohorts were unequal in size | |||
| Hou et al. (2013) | Medical records, 147 patients | The analytical data revealed that toxic hepatitis was common after APAP overdose, but the study failed to identify any significant risk factors for complications after ingestion. The favorable outcomes depend probably on a prompt diagnosis of poisoning and the immediate institution of detoxification protocols. | Small sample size |
| Short follow-up duration | |||
| Retrospective | |||
| Varney et al. (2014) | Multileft, retrospective, 37 patients | This study considered obese patients (>100 kg). Clinicians used a weight-based NAC dose rather than a maximum weight cut-off dose. Hepatotoxicity was common in our cohort. AEs were relatively common but not serious | Small number of heavy patients |
| Patients were not massively obese | |||
| Lack of height and BMI | |||
| Observational nature of the study | |||
| Curtis and Sivilotti (2015) | Observational case series, 68 patients | This study described AST and ALT rise and fall following acetaminophen overdose and discontinuation of NAC | Retrospective nature of the study |
| Limited number of deaths precluded a detailed comparison of AST/ALT in fatal events | |||
| Radosevich et al. (2016) | Retrospective cohort, 80 patients | Obese and nonobese patients being treated with I.V. NAC for APAP toxicity experienced similar rates of hepatotoxicity | Retrospective study |
| Limited data regarding APAP ingestion history | |||
| Limited number of obese patients | |||
| Yarema et al. (2018) | Retrospective cohort study, 6450 patients | Anaphylactic reactions to the 21-h I.V. NAC protocol were uncommon and involved primarily cutaneous symptoms. Being female and having taken a single, acute overdose was associated with more severe reactions, whereas higher serum APAP concentrations were associated with fewer reactions. | Retrospective study, with no available data for analysis (data about risk factors, such as asthma, atopy, family history of allergy, previous reactions) |
| They were not strong enough to impact the current clinical decision-making surrounding the initiation of NAC | Long interval between data collection and publication | ||
| Hospitalized patients, not from the emergency department |