Poisoning | Mechanisms of N-acetylcysteine Mediated Vascular Adverse Effects
Poisoning research study
What is the primary objective of this study?
Paracetamol overdose is the leading cause of acute liver failure in the Western World. N-acetylcysteine (NAC) has been the antidote of choice for over 30 years but its use is associated with adverse effects in 40% of cases. Patients characteristically experience nausea, vomiting and an anaphylactoid ('pseudo-allergic') syndrome. This reaction is clinically similar to true anaphylaxis (allergic reaction) including flushing, rash, constriction of airways, and a fall in blood pressure, but occurs via a different mechanism. Although treatable, these reactions lead to patient distress, commonly cause confusion among treating physicians, and lead to significant delays in antidote administration. The aetiology of these adverse reactions to NAC remains unclear. We hypothesise: i) these reactions result from a dose-dependent release of the chemical histamine, causing dilatation of blood vessels (vasodilatation) and the anaphylactoid syndrome; ii) paracetamol conversely exerts a protective effect on the reaction, with a less severe reaction observed in the presence of higher paracetamol concentrations. We will investigate the mechanisms underlying adverse reactions to NAC in the human forearm model, examining the role of histamine and other markers involved in the inflammatory process. The wider significance is an improved understanding of this poorly delineated phenomenon, with implications for other medications associated with similar reactions, such as non-steroidal anti-inflammatory drugs and opioids such as morphine.
Who is eligible to participate?
Inclusion Criteria: - Healthy male, non-smoking, volunteers aged between 18-64 years Exclusion Criteria: - Lack of informed consent Age <18 or >64 years Current smoker Current involvement in a clinical trial Clinically significant comorbidity: heart failure, hypertension, known hyper-lipidaemia, diabetes mellitus, asthma, coagulopathy or bleeding disorders Current intake of aspirin, other non-steroid anti-inflammatory medications, or vasodilators Recent infective/inflammatory condition Recent blood donation (during the preceding three months)
Which medical condition, disease, disorder, syndrome, illness, or injury is researched?
Interventions can include giving participants drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available or noninvasive approaches such as surveys, education, and interviews.
Drug:Chlorphenamine and RanitidineWe intend to use chlorphenamine (H1 antagonist) and ranitidine (H2 antagonist).Assuming NAC causes vasodilatation with an increase in forearm blood flow, we propose to administer 5 mcg/min to ensure maximal H1 blockade. In the presence of increased forearm blood flow, we propose to administer 37.5 mcg/min.
Drug:ParacetamolTherapeutic IV administration of 1g paracetamol results in a plasma concentration of ~12 mg/l. To achieve a desired concentration of ~25 mg/l, in the presence of a forearm blood blow of 50 ml/min, we would intend to administer an IA infusion of 1.25 mg/min. To account for the presence of increased forearm blood flow, we propose to administer 4 mg/min IA paracetamol.
Drug:ParacetamolTo achieve a local paracetamol concentration of ~200 mg/l, a concentration comparable to potentially hepatotoxic concentrations following paracetamol overdose, we propose to administer 30 mg/min paracetamol.
Research studies and clinical trials typically have two or more research arms. An arm is a group of people who receive the same treatment in the study.
SalineVolunteers will receive an incremental rising dose infusion of IA NAC (6 doses) together with a co-infusion of normal saline to determine a dose response curve for arterial vasodilatation in the forearm.
Histamine antagonistsSubjects will receive an increasing dose infusion of NAC as described in arm 1 but in this arm will receive a co-infusion of histamine antagonists (H1 and H2 antagonists) to determine vasodilatation in response to NAC in the presence of histamine antagonists.
Low dose paracetamolSubjects will receive an increasing dose infusion of NAC as described in arm 1 but in this arm will receive a co-infusion of low dose paracetamol to determine whether the vasodilatory response to NAC is inhibited.
High dose paracetamolSubjects will receive an increasing dose infusion of NAC as described in arm 1 but in this arm will receive a co-infusion of higher dose paracetamol to determine whether the vasodilatory response to NAC is inhibited.
Start Date: January 2011
Completed Date: September 2012
Primary Outcome: Attenuation of NAC induced vasodilatation by histamine antagonists (H1 and H2 antagonists) and/or paracetamol
Secondary Outcome: Inhibition of the inflammatory cascade contributes to a paracetamol mediated protective role against NAC adverse reactions.
Study sponsors, principal investigator, and references
Principal Investigator: Euan A Sandilands, MRCP BSc
Lead Sponsor: University of Edinburgh
Collaborator: NHS Lothian