NAC Regimen

Antidote for paracetamol poisoning is NAC. NAC replenishes cellular glutathione, which protects hepatocytes against injury from the toxic paracetamol metabolite N acetyl p benzoquinone imine (NAQPI). 

21h conventional NAC regimen developed by Prescott has been used since 1970's. The 21h NAC regimen is associated high incidence of anaphylaxis.  The complex regimen can lead to medication errors, frequent treatment interruption, prolonged stays. Since then only a few studies have been done to identify a alternative regimen. 

NAC IV Regime

1. Conventional Three Bag Regime 

• 150mg/kg in 5D over 15 minutes
• 50mg/kg in 500ML 5D over 4 hours
• 100mg/kg in 1L 5D over 16 hours

2. SNAP 12h Regimen ( Scottish and Newcastle Anti emetic Pretreatment for paracetamol poisoning study regimen) 

• 100mg/kg over 2 h in 200ml D5
• 200mg/kg over 10h 1L D5
• Followed by 5% Dextrose over 8h

• Thanacoody et al (BMC Pharmacology and Toxicology 2013) proposed that adverse effects of 21h regimen was related to high concentration of NAC following loading infusion.   Using the pharmacokinetic data from Prescot they performed a, Monte carlo stimulation to derive expected plasma concentration. Based on this data they estimated that the modified infusion (SNAP) regimen would rise the plasma concentration of 306, 122 and 30 mg/L at 2h, 12h and 20h respectively.
• SNAP Regimen will achieve a lower peak and a 20h plasma concentration comparable to conventional regimen. Anaphylactoid reaction is assumed to be dose dependent and pharmacokinetic data shows this occurs when NAC >650mg/L. Hence adverse events are believed to be less in the new regime. 

• Bateman et al (Lancet.2014) did a double blinded RCT to assess whether adverse effect could be reduced with modified regimen. The study found that 12h regimen resulted in lower vomiting and anaphylatoid reaction. 

• Pettie et al (EClinicalMedicine. 2019) did a study to assess the safety & efficacy of the SNAP 12 hour acetylcysteine regimen for paracetamol poisoning. They compared data of patients treated with 21h conventional regimen (n=1488) to new 12 h SNAP regimen (n=1852) . They found that there was no difference in liver injury or dysfunction in both regimen. Hepatotoxicty (ALT >1000 U/L) occured in 64 (4.3%) and 67 (3.6%) patients, respectively in 21h and SNAP regimen.

3. Simplified Two Bag Regime 

• 200mg/kg in 500ml D5 over 4 hours
• 100mg/kg in 1L D5 over 16 hours

• Wong et al (Clinical Toxicology. 2015 ) did a study to compare incidence of adverse drug events of two bag acetylcysteine regimen with that of traditional three bag regimen. The study found that 2 bag regimen was well tolerated and resulted in significantly fewer and milder adverse effects than 3 bag regimen. 

• Isbister et al (Clinical Toxicology. 2015 ) did a prospective observational study of a novel 2-phase infusion protocol for administration of acetylcysteine in paracetamol poisoning and found that 2 phase NAC infusion protocol results in fewer reactions. 

• Cole at al (West J Emerg Med. 2023) did a meta analysis and found 2 bag NAC regimen have similar outcome to the traditional three bag regimen. 

• Wong et al (Lancet.2020) 2NAC Study did a multicentric observational study done in 9 centres in Australia to compare the rate of ALI after paracetamol overdose in two bag regimen compared to three bag regimen. ALI was observed in 3.1% (21/668) with the two-bag regimen and 2.9% (16/557) with the three-bag regimen (Difference: 0.2%, 95%CI:−1.6 to 2.2). The incidence of hepatotoxicity was: 1.2% (n = 8) with the two-bag regimen and 1.6% (n = 9) with the three-bag regimen (Difference −0.4%, 95%CI −1.75 to 0.91). The incidence of peak INR >2.0 was 0.9% (n = 6) with the two-bag regimen vs 0.4% (n = 2) with the three-bag regimen (Difference: 0.5%, 95%CI −0.33 to 1.41). A two-bag intravenous acetylcysteine regimen was found to be non-inferior to the traditional three-bag regimen with regards to efficacy in preventing acute liver injury for early presentations of paracetamol overdose.

Stopping Criteria

• Treat with NAC until 
• Paracetamol levels < 10 mg/L
• AST or ALT < 100 u/l
• INR <2
• Patient is clinically stable and atleast 12h of NAC is given.

Conclusion

• Both 3 bag and 2 bag regimen is approved by US FDA for treating paracetamol poisoning. 2 bag regimen is recommended by clinical toxicology guidelines of New Zealand and Australia. 

Reference

• Thanacoody et al. BMC Pharmacology and Toxicology 2013, 14:20 http://www.biomedcentral.com/2050-6511/14/20

• Pettie JM, Caparrotta TM, Hunter RW, Morrison EE, Wood DM, Dargan PI, Thanacoody RH, Thomas SHL, Elamin MEMO, Francis B, Webb DJ, Sandilands EA, Eddleston M, Dear JW. Safety and Efficacy of the SNAP 12-hour Acetylcysteine Regimen for the Treatment of Paracetamol Overdose. EClinicalMedicine. 2019 May 2;11:11-17. doi: 10.1016/j.eclinm.2019.04.005. PMID: 31317129; PMCID: PMC6610779.

• Wong A, Isbister G, McNulty R et al. Efficacy of a two bag acetylcysteine regimen to treat paracetamol overdose (2NACstudy). eClinicalMedicine, 2020; 20

• Wong, A., & Graudins, A. (2016). Simplification of the standard three-bag intravenous acetylcysteine regimen for paracetamol poisoning results in a lower incidence of adverse drug reactions. Clinical Toxicology, 54(2), 115–119. https://doi.org/10.3109/15563650.2015.1115055

Early Vasopressors in sepsis .Is it beneficial ?

Starting vasopressors early in the management of sepsis, is it beneficial or harmful ?  This question has been haunting the Emergency Physician for quiet some time. Lets look at what the evidence tells us 

CENSER Trail AJRCCM.2019 was a single centre, randomised, double blinded, placebo controlled trial was done to evaluate if early low dose norepinephrine in adults with sepsis with shock improves shock control by 6 hours compared with standard care. Median time from emergency room arrival to norepinephrine  administration was significantly shorter in the early norepinephrine group (93 vs. 192 min; P , 0.001). Shock control rate by 6 hours was significantly higher in the early norepinephrine group (118/155 [76.1%] vs. 75/155 [48.4%]; P , 0.001). The 28-day mortality was not different between groups: 24/155 (15.5%) in the early norepinephrine group versus 34/155 (21.9%) in the standard treatment group (P =0.15). The early norepinephrine group was associated with lower incidences of cardiogenic pulmonary edema (22/155 [14.4%] vs. 43/155 [27.7%]; P = 0.004) and new-onset arrhythmia (17/155 [11%] vs. 31/155 [20%]; P = 0.03).Early norepinephrine was significantly associated with increased shock control by 6 hours.

CLOVERS Trail NEJM.2023 was done to asses whether a early restrictive fluid strategy ( Prioritizing vasopressors and lower IV fluid volumes) or a liberal fluid management was beneficial for sepsis induced hypotension.

Study found that the restrictive fluid group administrated -2134ml of IV Fluids less than liberal fluid group and vasopressor use was more longer in restrictive use. Death from any cause before discharge home by day 90 occurred in 109 patients (14.0%) in the restrictive fluid group and in 116 patients (14.9%) in the liberal fluid group (estimated difference −0.9 percentage points; 95% CI, −4.4 to 2.6; P=0.61).

Among patients with sepsis-induced hypotension, the restrictive fluid strategy that was used in this trial did not result in significantly lower (or higher) mortality before discharge home by day 90 than the liberal fluid strategy. 

ARISE Fluids Trail NEJM. 2026 randomly assigned adult patients who presented to the emergency department with septic shock to receive either fluids at restricted volumes and early vasopressor therapy (vasopressor group) or higher volumes of fluids and later vasopressor therapy (fluids group) for at least 6 hours and up to 24 hours. 

In the first 24 hours after randomization, patients in the vasopressor group received less intravenous fluid than those in the fluids group (median difference, −1108 ml; 95% confidence interval [CI], −1395 to −850). The percentage of patients who received vasopressors was  higher by 18.9 percentage points (95% CI, 13.3 to 24.5) in the vasopressor group. The median number of days alive and out of the hospital at day 90 was 76 (interquartile range, 55 to 83) in the vasopressor group and 76 (interquartile range, 55 to 82) in the fluids group (difference, 0.0 days; 95% CI, −2.7 to 2.7; P=1.00). Adverse events occurred in similar percentages of patients in the two groups, except 

for pulmonary edema (0.6% in the vasopressor group vs. 5.0% in the fluids group; P<0.001).

The study concluded that Among adult patients who presented to the emergency department with septic shock, an approach that involved restricted fluid volume and early vasopressors didnot result in a greater number of days alive and out of the hospital at day 90 than an approach involving greater fluid volume and later administration of vasopressors.

Conclusion

Evidences from these studies shows that early vasopressors may help to achieve  shock stabilisation early but studies have failed to show mortality benefit . At the same time liberal use of fluids have shown to be associated with adverse effects like pulmonary edema. 

But we need to understand that sepsis induced hypotension can be due to decrease in vascular resistance, capillary leak, cardiac dysfunction, decreased circulatory volume or combination of all. So what suits to one patient may not be suitable for another. So now the world is moving towards personalised hemodynamic resuscitation.

Tranexemic Acid Nebulisation, Does it have a role ?

•  Tranexemic acid (TXA) is a synthetic lysine analog that inhibits fibrinolysis by competitively binding sites of plasminogen and plasmin, thereby preventing the activation of plasminogen and its conversion to plasmin, reducing fibrin degradation and exerting a hemostatic effect.

• Systemic administration of TXA has been proven effective in treating pulmonary hemorrhage. Kinoshita et al (Critical care.2019) did a retrospective study to asses the effect of TXA (n=17049) on in hospital mortality among patients with hemoptysis against a control group (n=11490). Study found that patients treated with tranexemic acid  has significantly lower in-hospital mortality (11.5% vs. 9.0%; risk difference, − 2.5%; 95% confidence interval (CI), − 3.5 to − 1.6%), shorter hospital stays (18 ± 24 days vs. 16 ± 18 days; risk difference, − 2.4 days; 95% CI,− 3.1 to − 1.8 days).

• Recently few studies have shown nebulised therapy promising results. Nebulised therapy directly targets the respiratory tract and lungs, thereby reducing the local drug concentration, low dose, convenient application and few side effects. Nebulised therapy acts locally thereby reducing risk of thrombosis.

Evidence

• Wand et al (CHEST.2018) did a prospective RCT to assess the efficacy and safety of nebulized tranexemic acid in treating hemoptysis. The study compared nebulized TXA with placebo in patients with hemoptysis from various causes, excluding those with massive hemoptysis. The regimen involved nebulizing TXA at 500 mg/5 ml or 0.9% saline at 5 ml, three times a day. A total of 47 patients were included (25 in the TXA group and 22 in the placebo group). Results showed that, compared with those the placebo group, patients in the nebulized TXA group had a significant reduction in hemoptysis volume from the second day of admission, with a higher rate of hemoptysis resolution within 5 days of admission (96% vs 50%; P < 0.0005).

• Gopinath et al (CHEST. 2023) did a  pragmatic, open-label, randomized, parallel, single-center, pilot trial of nebulized TA (500 mg tid) vs IV TA (500 mg tid) in adult patients presenting to the ED with active hemoptysis.The results revealed that the 30-min hemoptysis cessation rate in the nebulized TXA group (72.72%) was significantly higher than that in the intravenous TXA group (50.91%). Additionally, the amount of hemoptysis in the nebulized group was significantly reduced at all observed time points. With respect to safety, no significant adverse reactions occurred in either group.

Reference

• Zhang, P., Zheng, J., Shan, X. et al. Advances in the study of nebulized tranexamic acid for pulmonary hemorrhage. Eur J Clin Pharmacol 81, 237–246 (2025). https://doi.org/10.1007/s00228-024-03784-5
• Kinoshita, T., Ohbe, H., Matsui, H. et al. Effect of tranexamic acid on mortality in patients with haemoptysis: a nationwide study. Crit Care 23, 347 (2019). https://doi.org/10.1186/s13054-019-2620-5
• Gopinath B, Mishra PR, Aggarwal P, Nayaka R, Naik SR, Kappagantu V, Shrimal P, Ramaswami A, Bhoi S, Jamshed N, Sinha TP, Ekka M, Kumar A. Nebulized vs IV Tranexamic Acid for Hemoptysis: A Pilot Randomized Controlled Trial. Chest. 2023 May;163(5):1176-1184. doi: 10.1016/j.chest.2022.11.021. Epub 2022 Nov 19. PMID: 36410494.

AHA Focus Update on Life Threatening Toxicity 2023

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