Haemodynamic Effects Of Intravenous Paracetamol In Healthy Volunteers

Intravenous paracetamol is ubiquitously used in hospitals as an antipyretic and analgesic worldwide. It is administered to a wide array of patients including those undergoing major surgeries and the critically ill due to its minimal side effect profile. However, recent studies have provided compelling evidence for a re-evaluation of paracetamol use in this setting as it has been found to cause hypotension in intensive care patients. Importantly, there is a paucity of guidance regarding its haemodynamic safety in surgical and critically ill patients. This may be due to a lack of double-blinded, randomised controlled trials in these settings as well as in healthy patient cohorts for comparative studies. In addition, a previous study found that oral effervescent paracetamol tablets produced hypertension in patients which study investigators linked to the high sodium content in the effervescent formulation. It is therefore important to acknowledge that excipients (pharmacologically inactive compounds that act as vehicles for the active compound in the drug) may affect blood pressure. There is no existing literature that has addressed the potential for the high mannitol content of intravenous paracetamol to produce haemodynamic effects. Hypothesis: Paracetamol (1g IV) and mannitol (3.91g mannitol IV) will have adverse effects on blood pressure in healthy volunteers compared to 0.9% normal saline. No of participants: 24 No of recruiting hospitals: 1 Randomization: In this triple-cross over study, participants will be randomized in a 1:1:1 fashion via a computer generated randomization program to receive 1 treatment from each of the treatment arms. The treatment arms include: 1) Control (100mL 0.9% normal saline) 2) IV paracetamol (100mL paracetamol and mannitol 3.91g) 3) IV Mannitol treatment (100ml mannitol 3.91g) Blinding: This is a double-blinded clinical trial. This study requires the use of 100mL blinded fluid vials. These vials will look identical in all treatment groups. Depending on randomization, IV paracetamol, 0.9% normal saline or mannitol will be transferred into the blinded vials just prior to IV infusion. Preparation of the blinded vials will be conducted by an anaesthesia nurse who will not be involved in the data collection. The participants, sampling anaesthetist and data analyst will be blinded to the assignment of treatment. Primary endpoint: Changes in haemodynamics: Mean, systolic and diastolic blood pressure Secondary endpoints: Cardiac output and cardiac index, stroke volume, systemic vascular resistance, plasma osmolality Other data collected: Patient characteristics and adverse events