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Three Part Question

In an Adult who has taken an [acute clinically significant paracetamol overdose] requiring treatment, does[ reducing the rate of the initial dose of NAC], [reduce adverse effects]?

Clinical Scenario

Whilst on a clinical shift in the Emergency Department you attend to a 24 year old female who has taken a clinically significant paracetamol overdose, and requires n-acetylcysteine (NAC), you are wondering if a reduction in infusion rate of NAC will reduce adverse side effects such as vomiting and nausea?

Search Strategy

Ovid MEDLINE 1946 to present
EMBASE 1974 to 2018 January 10

paracetamol.mp OR acetaminophen/.exp OR paracetamol sulpahte.mp OR paracetamol derivative.mp AND Drug Overdose.exp OR Overdose.mp OR Poisoning.mp.exp OR “Chemical and drug induced Liver Injury”.exp OR paracetamol overdose.mp OR suicide, attempted.exp, OR self harm.mp or Suicide.exp AND acetlyceysteine.exp.mp OR NAC.mp OR antidote.mp OR antidotes.exp OR n-acetylcysteine.mp

Limits: English Language and Humans

Search Outcome

This search strategy found 784 results, of which 4 papers appear relevant and are included in table 1. (all papers compare their new regimes to the same old regime specified (a))

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Bateman et al, 2013, UK	Adults presenting to the emergency department with confirmed paracetamol overdose <8 hours from ingestion. ‘New regime’ Rate: 50mg/kg/hr Duration: 120 mins Dose: 100mg/kg Volume 200ml 0.9%NaCl Concentration: 0.5mg/kg/ml	Multi-centre double blinded randomised control trial, 2x2 design with different regimes of NAC and empirical vs symptomatic prescription of anti-emetics Σn = 222 n(old) = 110 n(new) = 112	Presence of vomiting, retching, use of rescue anti-emetic.	Old regime 65% New regime 36% OR 0.26 (0.13-0.52) p value = <0.0001	This trial was not powered to show non-inferiority of one regime over the other. Primary outcome is the most common NAAR however it did not capture all NAARs.
			Severe anaphylactoid reactions – defined as treatment interruption or anti-allergy medication prescribed	Old regime 4.6% New regime 31% OR 0.23 (0.12-0.43) P<0.0001
Bateman et al, 2014, UK	Adult patients presenting to the Emergency Department with confirmed paracetamol overdose. The properties of the first infusion of the two treatment groups ‘Old regime’ Rate: 600mg/kg/hr Duration: 15 mins Dose: 150mg/kg Volume 200ml 0.9&NaCl Concentration 0.75mg/kg/ml	A multivariate analysis of a prospective non-randomised consecutive study Σn = 837 n(old)=323 n(new)=514	1. Rate of anti-emetic prescription 2. Rate of anaphylaxis to NAC	The multivariate analysis concluded no difference in either outcome between the two treatment groups. 1. OR 0.85 (0.61-1.2) p value = 0.367 2. OR 1.22 (0.75-1.98) p value = 0.414	The multivariate analysis did not explore the rate of all adverse drug reactions. The outcome of use of anti-emetics relies on a clinician noting and responding to emesis / nausea. It is not clear why only 837 patients were included in the multivariate
Isbister et al, 2016, Australia	Adult patients presenting to the Emergency Department with suspected paracetamol overdose. The regime was started on admission and prior to first paracetamol serum level. Below are the properties of the new regimes first infusion: ‘New regime’ Rate: 22mg/kg/hr Duration: 540 mins Dose: 200mg/kg Volume unknown Concentration: unknown	Multi-site prospective observational study - all patients received the new regime Σn = 654	Gastrointestinal reactions	GI reactions 32.4% (28.9-36.2)	No control group Regime is based upon a published paper that used a computer model to validate the efficacy and safety. Proportion of regimes stopped on receipt of first paracetamol level - 64% (420) This regime raises the ethical dilemma of the individual versus the population. The population as a whole had a lower rate of adverse reactions (compared to the literature) however patients who would not have received NAC under previous regimes did and 28% of them experienced side effects.
			Systemic hypersensitivity reactions, (cutaneous, respiratory, and cardiovascular)	) Systemic hypersensitivity reaction - 8% (6.1-10.4)
			Severe anaphylaxis – hypotension and shortness of breath / hypoxia.	Severe anaphylaxis 0.5% (0.1-1.5)
Wong et al, 2016, Australia	Adult patients presenting to the Emergency Department with confirmed paracetamol overdose, above the treatment line. ‘New regime’ Rate: 50mg/kg/hr Duration: 240 mins Dose: 200mg/kg Volume 500ml 0.9%NaCl Concentration: 0.4mg/kg/ml	Multi-site retrospective case note analysis of a change in protocol Σn = 599 n(old) = 389 n(new) = 210	Non-allergic anaphylactic reactions (NAARS) to NAC – cutaneous/ respiratory / cardiovascular	NAARS outcome Old regime 10% New regime 4.3% OR 2.5 (1.1-5.8) p value = 0.02	The case note search strategy used did not include mixed overdoses and also relied on accurate medical records. It was noted that there was a lower incidence rate than expected for NAARS
			Gastrointestinal symptoms of nausea or vomiting	Gastrointestinal symptom: Old regime 39% New regime 41% OR 1.17 (0.83-1.65) P value = 0.38

Comment(s)

These four studies each compare their individual new NAC regimes against the same old regime, seeking improvement in adverse reaction rates. The commonality of the new regimes is that they all have a slower NAC infusion rate, and the outcomes all measure adverse reactions (gastrointestinal symptoms, systemic hypersensitivity reaction, severe anaphylaxis). These studies do differ slightly with different slower new regimes of NAC, and varying outcome definitions. Bateman et al’s (2013) randomised control trial and Wong et al’s demonstrate a statistically significant improvement in systemic adverse reactions (severe anaphylactoid reactions and non-allergic anaphylactic reactions) yet they differ on the new regimes effect on the rates of GI symptoms which could be due to study design and definition of outcomes. Isbister et al compares its results to literature values, the absolute rates of GI symptoms, severe systemic reactions and severe anaphylaxis do appear lower than ‘old regime’ referenced values however the statistical significance and comparability of this is unknown due to the absence of a control group. A multi-variate analysis by Bateman et al (2014) demonstrated no difference in rates of GI symptoms or anaphylactic reactions yet it did have the highest rate of infusion for any new NAC regime (150mg/kg/hr compared to the old of 200mg/kg/hr).

Editor Comment

SC

Clinical Bottom Line

The rate of adverse reactions to n-acetylcysteine are reduced by decreasing the infusion rate of the first bag, however the clinical parity of the old regime versus the new has not been comprehensively proven.

References

1. Bateman DN, Dear JW, Thanacoody HKR et al. Reduction of adverse effects from intravenous acetylcysteine treatment for paracetamol poisoning: a randomised controlled trial. The Lancet. 2013 Feb 22;383(9918):697–704.
2. Bateman DN, Carroll R, Pettie J et al. Effect of the UK’s revised paracetamol poisoning management guidelines on admissions, adverse reactions and costs of treatment. Br J Clin Pharmacol. 2014 Sep;78(3):610–8.
3. Isbister GK, Downes MA, Mcnamara K et al. A prospective observational study of a novel 2-phase infusion protocol for the administration of acetylcysteine in paracetamol poisoning. Clin Toxicol Phila Pa. 2016;54(2):120–6.
4. Wong A, Graudins A. Simplification of the standard three-bag intravenous acetylcysteine regimen for paracetamol poisoning results in a lower incidence of adverse drug reactions. Clin Toxicol Phila Pa. 2016;54(2):115–9.