Table 2.
Evidence for improved outcomes with two-bag intravenous N-acetylcysteine regimens.
| Outcomes | |||||||
|---|---|---|---|---|---|---|---|
|
Study (Total n = 14,618) |
Study type |
2-bag NAC regimen studied |
Primary outcome |
NAARs |
Hepatotoxicity |
Dosing errors |
Delays in treatment |
| Studies evaluating NAARs as primary outcome | |||||||
| Bateman et al. 2014 (“SNAP Trial”) 8 (n = 217) | RCT (adults) | SNAP (n = 108) vs. Prescott Protocol (n = 109) | Reduction in vomiting (including retching or need for antiemetics) in first 2 hours (36.1% vs. 65.1%; aOR = 0.26, [97.5% CI: 0.13–0.52], NNT = 3) | Reduction in clinically relevant severe * NAARs (4.6% vs. 31%; aOR = 0.23, [97.5% CI: 0.12–0.43], NNT = 4) | No difference in 50% increase in ALT between the groups (12.9% vs. 9%; aOR = 0.60, [97.5% CI: 0.20–1.83]) | NA | NA |
| Wong & Graudins. 2016 9 (n = 599) | Retrospective cohort | 2-bag/20-hours (n = 210) vs. Prescott Protocol (n = 389) | Fewer overall NAARs (4.3% vs 10%, OR = 2.5, [95% CI: 1.1–5.8], NNT = 18) | Fewer severe ** NAARs (0.5% vs. 1.8% [p < 0.01], NNT = 76) | No difference in hepatotoxicity (ALT >1,000 IU/L) (5.2% vs. 4.3%, p = 0.68, OR = 1.2, [95% CI: 0.55–2.63]) | NA | NA |
| Isbister et al. 2016 10 (n = 654) | Prospective observational (no comparison except to historical data) | Modified 2-bag based on ingestion time (n = 654) | Frequency of systemic hypersensitivity reactions = 8% (95% CI: 6–10%), lower than most previously published prospective studies of the Prescott protocol. | GI side effects similar to historic rates | 16 patients had an ALT >1,000 IU/L | Four errors related to NAC; three of which involved incorrect infusion rate of bag #1. | NA |
| McNulty et al. 2018 17 (n = 476) | Prospective data compared to historic controls | 2-bag/20-hours (n = 163) vs. Prescott Protocol (n = 313) | Fewer NAARs; 14% vs 5% (difference: 9.4% [95% CI: 4.3–14.6%], p = 0.002, NNT = 11) | Fewer severe *** NAARs; 8% vs. 2% (difference: 6.1% [95% CI: 2.5 −9.8%], p = 0.007, NNT = 17) Fewer anti-allergy medications; 11% vs. 4% (difference: 6.9% [95% CI: 2.4–11.3%], p = 0.01, NNT = 15) | No difference in incidence of hepatotoxicity (4.8% vs. 3.7%) | NA | NA |
| Schmidt et al. 2018 18 (n = 767) | Retrospective cohort | 2-bag/20-hours (n = 493) vs. Prescott Protocol (n = 274) | Fewer NAARs; 17% vs 4% (difference = −12.8%, 95% CI:−17.6%–−8.0%, p < 0.01, NNT = 8) | Fewer severe NAARs (hypotension, edema, respiratory symptoms); 0.6% vs. 4% (p = 0.003, NNT = 30) Fewer cutaneous NAARs: 2% vs. 14% (p < 0.001, NNT = 9) | No difference in hepatotoxicity (4% vs. 4%, difference: 0%, 95% CI:−2.9%–3.0%) | Medication errors were rare (1%) | Fewer interruptions or delays in NAC; 5% vs. 12% (difference: 6.6% [95%CI: 2.2–10.9%], p = 0.002, NNT = 15) |
| Daoud et al. 2020 19 (n = 4,315) | Retrospective cohort | 2-bag/20-hours (n = 2,951) vs. Prescott Protocol (n = 1,364) | 2-bag/20 hour NAC protocol associated with significantly fewer NAARs requiring treatment. (OR = 0.36 [95%CI: 0.28–0.46], 4% vs. 10.4%, NNT = 16) | Fewer life-threatening reactions (severe hypotension or airway-threatening angioedema): 0.6% vs. 0.14% Meta-analysis conducted revealed fewer NAARs with 2-bag regimens published to date. | NA | NA | NA |
| Sudanagunta et al. 2023 21 (n = 243) | Retrospective cohort (children age <18 years) | 2-bag/20-hours (n = 93) vs. Prescott Protocol (n = 150) | No overall difference in NAARs: 19% 2-bag vs. 23% 3-bag (p = 0.54) | NAARs Sub-analyses favoring 2-bag/20-hour protocol: Cutaneous NAARs: 2% vs. 10% (p = 0.02, NNT = 13) Fewer antihistamines administered for NAARs: 8% vs. 16% (p = 0.05, NNT = 13) | NA | Fewer NAC medication errors: 23% vs. 39% (p = 0.01, NNT = 7) | Majority of medication errors were due to timing defined as delays or pauses in NAC >1 hour |
| Studies evaluating hepatotoxicity as primary outcome | |||||||
| Pettie et al. 2019 22 (n = 3,340) | Prospective observational | SNAP (n = 1,852) vs. Prescott Protocol (n = 1,488) | No difference in liver injury, synthetic dysfunction, or hepatotoxicity (peak ALT >1,000 IU/L) | Fewer antihistamines given for NAARs; 11.0% vs. 2.0% (difference 9.0% [95% CI: 7.3–10.7], NNT = 10) | 4.3% Prescott Protocol vs. 3.6% SNAP (difference −0.7%; 95% CI: −2.1–0.6%) | NA | NA |
| Wong et al. 2020 (“2NAC study”)
11
(n = 2,211
*
) * Single, acute ingestions included in non-inferiority analysis. 2,763 patients received NAC, however in 552 cases the dosing regimen was not specified |
Retrospective cohort | 2-bag/20-hours (n = 1,300) vs. Prescott Protocol (n = 911) | No difference in acute liver injury (peak ALT > 150 IU/L), regardless of time of presentation or peak [APAP]. | Fewer NAARs; 7.1% vs. 1.3% (difference: 5.8% [95% CI: 4.0–7.6%], p < 0.0001, NNT = 18) Fewer GI side effects; 31% vs. 19% (p < 0.0001, NNT = 9) | No difference in hepatotoxicity (1.2% 2-bag vs. 1.6% 3-bag, difference: −0.4%, 95% CI: −1.75–0.91) | NA | NA |
| Syafira et al. 2022
20
(n = 887) |
Retrospective cohort (only patients receiving NAC within 8 hours of ingestion | 2-bag/20-hours (n = 191) vs. Prescott Protocol (n = 696) | No difference in acute liver injury (peak aminotransferase > 150 IU/L): 1.6% 2-bag vs. 2.2 – 2.9% 3-bag (difference, 0.6%, OR 0.7 [95%CI: 0.2–2.6]) | NA | No difference in hepatotoxicity (peak ALT >1,000 IU/L) between groups. Significantly higher proportion of patients with elevated aminotransferases (peak aminotransferase > 40 IU/L) in one of two 3-bag regimen cohorts: 14.8% vs. 3.7% (difference, 11.1%, OR = 0.2 [95%CI: 0.01–0.5], NNT = 10) | NA | NA |
| Studies evaluating delays in treatment as primary outcome | |||||||
| O’Callaghan et al. 2022 12 (n = 869) | Retrospective cohort | 2-bag/20-hours (n = 598) vs. Prescott Protocol (n = 271) | Shorter median cumulative delays in NAC administration: 35 vs. 65 minutes (absolute difference: 30 minutes [95%CI: 20 – 33], p < 0.01) | Fewer GI side effects: 76% vs. 56% (p < 0.0001, NNT = 5) Fewer cutaneous NAARs: 4.2% vs. 10% (p < 0.0001, NNT = 18) Fewer systemic NAARs: 4.1% vs. 0.8% (p < 0.001, NNT = 31) | Higher median ALT (40 IU/L vs. 19 IU/L) in patients receiving the 3-bag regimen with delays > 3 hours | NA | Delays inNAC administration > 1 hour less common with 2-bag (31% vs. 51%, p < 0.01, NNT = 5) |
| Studies evaluating serum sodium levels as primary outcome | |||||||
| Oakley et al. 2011 16 (n = 40) | Case series (children ≤17 years) | 150 mg/kg over one hour, then 10 mg/kg/hr for 20 hours (n = 40) | Serum sodium remained in normal range using 0.45% saline as the NAC diluent rather than D5W to prevent iatrogenic hyponatremia in children. | 18 patients (49%) had any adverse reaction. | NA | NA | NA |
*
Clinically significant NAARs: requiring drug treatment or interruption of NAC infusion.
**
Severe NAARs: angioedema, bronchospasm, or hypotension.
***
Severe NAARs: hypotension, dyspnea, swelling.
RCT, randomized controlled trial; SNAP, Scottish and Newcastle Antiemetic Pre-treatment for Paracetamol Poisoning; NAC, N-acetylcysteine; OR, odds ratio; aOR, adjusted odds ratio; CI, confidence interval; NNT, number needed to treat; NAARs, non-allergic anaphylactoid reactions, which in some studies include both gastrointestinal and systemic effects; ALT, alanine aminotransferase; GI, gastrointestinal; D5W, dextrose 5% in sterile water.