The haemodynamic effects of intravenous paracetamol (acetaminophen) in healthy volunteers: a double‐blind, randomized, triple crossover trial

Abstract

Aim The haemodynamic effects of intravenous paracetamol have not been systematically investigated. We compared the physiological effects of intravenous mannitol‐containing paracetamol, and an equivalent dosage of mannitol, and normal saline 0.9% in healthy volunteers. Methods We performed a blinded, triple crossover, randomized trial of 24 adult healthy volunteers. Participants received i.v. paracetamol (1 g paracetamol +3.91 g mannitol 100 ml–1), i.v. mannitol (3.91 g mannitol 100 ml–1) and i.v. normal saline (100 ml). Composite primary end points were changes in mean arterial pressure (MAP), systolic blood pressure (SBP) and diastolic blood pressure (DBP) measured pre‐infusion, during a 15 min infusion period and over a 45 min observation period. Systemic vascular resistance index (SVRI) and cardiac index were measured at the same time points. Results Infusion of paracetamol induced a transient yet significant decrease in blood pressures from pre‐infusion values (MAP –1.85 mmHg, 95% CI –2.6, –1.1, SBP –0.54 mmHg, 95% CI –1.7, 0.6 and DBP −1.92 mmHg, 95% CI –2.6, –1.2, P < 0.0001), associated with a transient reduction in SVRI and an increase in cardiac index. Changes were observed, but to a lesser extent with normal saline (MAP –0.15 mmHg, SBP +1.44 mmHg, DBP −–0.73 mmHg, P < 0.0001), but not with mannitol (MAP +1.47 mmHg, SBP +4.03 mmHg, DBP +0.48 mmHg, P < 0.0001). Conclusions I.v. paracetamol caused a transient decrease in blood pressure immediately after infusion. These effects were not seen with mannitol or normal saline. The physiological mechanism was consistent with vasodilatation. This study provides plausible physiological data in a healthy volunteer setting, supporting transient changes in haemodynamic variables with i.v. paracetamol and justifies controlled studies in the peri‐operative and critical care setting.

Haemodynamic changes with paracetamol in critically-ill children

“…The observed blood pressure effect of paracetamol is likely due to a reduction in vascular resistance, as has been reported in previous adult studies 7,8 . This is consistent with the hypothesis that paracetamol may release the vasoconstriction induced by fever.…”

“…The mechanism behind this is unknown: Chiam et al hypothesised that this reduction may be due to SV changes secondary to mannitol used as a stabilizer in most intravenous paracetamol formulations. However in a randomised controlled trial of healthy volunteers, Chiam et al did not observe this effect: cardiac index increased in their experiment with both paracetamol and a dose equivalent mannitol infusion 7 . However the time course of blood pressure change we describe in our patients is different.…”

“…The haemodynamic mechanism for this blood pressure decrease has been explored using various methods. Some authors have reported a reduction in cardiac output -either due to a reduction in heart rate 6 , or due to the diuretic effect of mannitol present in intravenous paracetamol preparations 7 . However, there is also evidence to suggest that the reduction in blood pressure is related to a decrease in the systemic vascular resistance (SVR): (a) peripheral blood flow increases when measured using laser Doppler flowmetry in febrile patients 8 ; and (b) a reduction in SVR has been observed following paracetamol administration when measured in a randomised controlled trial of healthy volunteers, but not after an equivalent dose of mannitol alone was given 7 .…”

Clinical pharmacology of analgosedatives in neonates: ways to improve their safe and effective use

“…Undesired short‐term side effects of paracetamol described in other populations mainly relate to hemodynamics or hepatotoxicity and have mainly been documented in (pre)term neonates > 32 weeks, with only limited data in extreme preterm neonates. The hemodynamic side effects of intravenous paracetamol in neonates are very modest and likely explained by a transient reduction in systemic vascular resistance . Prospective data suggest good hepatic tolerance .…”

How publication guidelines for clinical pharmacology trials may help to accelerate knowledge transfer

“…Independent hospital pharmacy staff provided the solutions in identical unmarked blinded vials. Treatment allocation was only revealed after data analysis was performed [11].…”