Table 3.
Studies evaluating non-allergic anaphylactoid reactions in two-bag intravenous N-acetylcysteine regimens.
| Specific NAARs | |||||||
|---|---|---|---|---|---|---|---|
|
Study (Total N = 13,731) |
Study type |
2-bag NAC regimen studied |
NAARs definitions |
GI effects |
Total NAARs and/or systemic NAARs |
Skin-only reactions |
Anti-allergy medications administered as treatment |
| Studies with comparative data 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 hoursAnaphylactoid reactions, defined as need for treatment or NAC interruption; self-reported flushing, itchy skin, rash, chest pain, dyspnea, wheezing, tongue/lip swelling | 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) Fewer total anaphylactoid reactions (54% vs. 75%) | NA | NA |
| Wong and Graudins. 2016 9 (n = 599) | Retrospective cohort | 2-bag/20-hours (n = 210) vs. Prescott Protocol (n = 389) | NAARs classified into cutaneous (flushing, rash, urticaria. Wheals, itch) and more severe reactions including respiratory symptoms (bronchospasm, wheeze, dyspnea) and angioedema or cardiovascular instability (i.e., hypotension) GI symptoms included nausea or vomiting. | No difference in gastrointestinal side effects (2-bag = 41%, 3-bag = 39%) | Fewer severe ** NAARs (0.5% vs. 1.8% [p < 0.01], NNT = 76) Fewer overall NAARs (4.3% vs 10%, OR = 2.5, [95% CI: 1.1–5.8], NNT = 18) | Fewer reactions (8%) with 2-bag compared to 3-bag (33%) | Assessed for but not reported |
| McNulty et al 2018 17 (n = 476) | Prospective data compared to historic controls | 2-bag/20-hours (n = 163) vs. Prescott Protocol (n = 313) | Cohorts compared for adverse reactions to NAC (not further defined), or use of anti-allergy medications | No difference in gastrointestinal side effects (3-bag = 37%, 2-bag = 31%). | 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) | No difference in skin-only reactions (3-bag = 6%, 2-bag = 3%, p = 0.12) | Fewer anti-allergy medications; 11% vs. 4% (difference: 6.9% [95% CI: 2.4 – 11.3%], p = 0.01, NNT = 15) |
| Schmidt et al 2018
18
(n = 767) |
Retrospective cohort | 2-bag/20-hours (n = 493) vs. Prescott Protocol (n = 274) | Cutaneous (flushing, rash, urticaria, wheals, itch), severe reactions (bronchospasm, wheeze, dyspnea) and angioedema or cardiovascular instability (i.e., hypotension). Intensity of symptoms rated as mild (aware of signs/symptoms but easily tolerated), moderate (discomfort to interfere with usual activity), severe (incapacitating with inability to work or do usual activity) or unknown. | No difference in gastrointestinal side effects (3-bag = 1%, 2-bag = 0%). | 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) | Assessed for but not reported |
| Daoud et al 2020 19 (n = 4,315) | Retrospective cohort | 2-bag/20-hours (n = 2,951) vs. Prescott Protocol (n = 1,364) | Defined as a reaction requiring treatment with IV antihistamine and/or glucocorticoids | GI effects rare for both groups, no difference found: 2-bag = 0.24%, 3-bag = 0.51%, p = 0.14 | 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% | Fewer cutaneous reactions with 2-bag (2.9%) vs. 3-bag (7.7%), p < 0.0001 | Fewer medications needed to treat NAARs with 2-bag (6.9%) vs. 3-bag (19.7%), p < 0.0001 |
| Sudanagunta et al 2023 21 (n = 243) | Retrospective cohort (children age <18 years) |
2-bag/20-hours (n = 93) vs. Prescott Protocol (n = 150) | NAARs divided into 4 organ systems (cutaneous, cardiovascular, GI, respiratory), keywords searched for in chart (e.g., urticaria, wheal, edema, bronchospasm, wheeze, nausea, vomiting, hypotension) | No difference in GI symptoms: (3-bag = 11%, 2-bag = 11%) | No overall difference in NAARs: 19% 2-bag vs. 23% 3-bag (p = 0.54) | Fewer cutaneous NAARs: 2% vs. 10% (p = 0.02, NNT = 13) | Fewer antihistamines administered for NAARs: 8% vs. 16% (p = 0.05, NNT = 13) |
| Studies with comparative data evaluating NAARs as a secondary outcome | |||||||
| Pettie et al 2019 22 (n = 3,340) | Prospective observational | SNAP (n = 1,852) vs. Prescott Protocol (n = 1,488) | Antihistamine prescribing was used to estimate the rate of anaphylactoid reactions. | NA | Fewer antihistamines given for NAARs; 11.0% vs. 2.0% (ARR = 9.0% [95% CI: 7.3–10.7], NNT = 10) | NA | See total NAARs; sub-analysis of 37 patients receiving both regimens for multiple overdoses (198 admissions, 81 received 3-bag, 117 received SNAP), found NAARs occurred in 6.2% of 3-bag admissions and in 0.9% of SNAP admissions (ARR = 5.3%, 95% CI: 0.1–12.8%) |
| Wong et al 2020 (“2NAC study”)
11
(n = 2,211
*
) * Single, acute ingestions included in non-inferiority analysis. 2,763 patients got 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) | NAARs classified into cutaneous (flushing, rash, urticaria, itch), more severe reactions (bronchospasm, wheeze, dyspnea, angioedema, cardiovascular instability [i.e., hypotension]), and GI symptoms (nausea, vomiting, or both) | Fewer gastrointestinal side effects; 31% vs. 19% (p<0.0001, NNT = 9) | Fewer Cutaneous and Systemic NAARs: combined data 7.1% vs. 1.3% (difference: 5.8% [95% CI: 4.0–7.6%], p < 0.0001, NNT = 18) | Fewer Cutaneous NAARs: (2-bag, 1.1% vs. 3-bag, 6.4%) | NA |
| O’Callaghan et al 2022 12 (n = 869) | Retrospective cohort | 2-bag/20-hours (n = 598) vs. Prescott Protocol (n = 271) | Adverse reactions assessed in three categories: gastrointestinal (nausea/vomiting/retching), cutaneous (rash/itch/flushing), and systemic (bronchospasm/hypotension/angioedema or administration of medications) | Fewer gastrointestinal side effects: 76% vs. 56% (p < 0.0001, NNT = 5) | Fewer systemic NAARs: 4.1% vs. 0.8% (p < 0.001, NNT = 31) | Fewer cutaneous NAARs: 4.2% vs. 10% (p < 0.0001, NNT = 18) | Assessed for but not reported individually |
| Single-arm studies evaluating non-allergic anaphylactoid reactions. | |||||||
| 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) | Not defined | 11 patients (30%) had vomiting. | 18 patients (49%) had any adverse reaction. One patient each (2.5%) had breathlessness, abdominal pain, and cough. | Four (11%) patients developed rash. | 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) | Primary outcome was proportion of patients with adverse reactions, including only GI symptoms (not further defined) and the proportion with systemic hypersensitivity reactions, defined as either skin only or non-immune mediated anaphylaxis as defined by NIAID-FAAN. Severe anaphylaxis reactions were defined by hypotension or hypoxia | Gastrointestinal side effects similar to historic rates (26.5%) | Frequency of systemic hypersensitivity reactions = 8% (95% CI: 6–10%), lower than most previously published prospective studies of the Prescott Protocol. 0.5% had severe anaphylaxis | 8% had skin-only reactions | 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; GI, gastrointestinal, 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, ARR, absolute risk reduction, NIAID-FAAN, National Institute of Allergy and Infectious Diseases/Food Allergy and Anaphylaxis Network.