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Trial registered on ANZCTR

Registration number

ACTRN12615000533594

Ethics application status

Approved

Date submitted

21/01/2015

Date registered

27/05/2015

Date last updated

5/02/2016

Type of registration

Retrospectively registered

Titles & IDs

Public title

Haemodynamic Effects Of Intravenous Paracetamol In Healthy Volunteers

Scientific title

Haemodynamic Effects Of Intravenous Paracetamol In Healthy Volunteers

Secondary ID [1]

NIL

Universal Trial Number (UTN)

U1111-1166-3985

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Blood pressure in Healthy Volunteers

Cardiac output in Health Volunteers

Systemic vascular resistance in Healthy volunteers

Condition category

Condition code

Cardiovascular

Normal development and function of the cardiovascular system

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Paracetamol is one of the most commonly used medications in the world. The intravenous formulation is the preferred method of administration in the intraoperative and immediate postoperative periods.

1 gram of Intravenous paracetamol (Actavis, North Adelaide, SA) is manufactured in a 100 ml vial that contains the following in its formulations:
Paracetamol = 1g, Mannitol = 3.91g, Cysteine hydrochloride monohydrate, Dibasic dihydrate, sodium phosphate, sodium hydroxide, hydrochloric acid, water for injections

It is unknown if intravenous paracetamol results in adverse effects of haemodynamics i.e blood pressure, cardiac output, stroke volume and systemic vascular resistence

Therefore we will perform a triple crossover study to investigate this question.

Each healthy volunteer will receive the following 3 interventions on 3 separate days. The days will be between 1 and 7 days part. i.e there will be a washout period of between 1 and 7 days. The infusions will be administered over a 15 minute period.

The three interventions are:

1. 1 gram intravenous paracetamol (Actavis, North Adelaide, SA) (100 ml total volume)
2. Mannitol 3.9 grams (100 ml total volume)
3. Normal saline (0.9%) (100 ml total volume)

A non-invasive haemodynamic monitoring device (Edwards Lifescience Nexfin Clearsite) will be attached to the participant's wrist and middle finger. It will continuously monitor the participant's blood pressure (mean, systolic and diastolic), cardiac output, stroke volume and systemic vascular resistance.

The effects of intravenous paracetamol on haemodynamics will be measured before the infusion, during the 15 minute infusion, and for 60 minutes after the infusion.

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

Mannitol 3.9 grams intravenously (administered in 100mL of distilled water over a 15 minute period)

Saline (0.9%) intravenously (administered in 100mL of distilled water over a 15 minute period)

Control group

Placebo

Outcomes

Primary outcome [1]

Systolic blood pressure using the Edwards Lifesciences ClearSite Advanced haemodynamic monitor.

Timepoint [1]

Baseline just before administration of each intervention;
During the 15 minute infusion period of each intervention;
For 60 minutes after the infusions have been administered.

Primary outcome [2]

Diastolic blood pressure measured using the Edwards Lifesciences ClearSite Advanced haemodynamic monitor

Timepoint [2]

Baseline just before administration of each intervention;
During the 15 minute infusion period of each intervention;
For 60 minutes after the infusions have been administered.

Primary outcome [3]

Mean arterial blood pressure measured using the Edwards Lifesciences ClearSite Advanced haemodynamic monotoring

Timepoint [3]

Baseline just before administration of each intervention;
During the 15 minute infusion period of each intervention;
For 60 minutes after the infusions have been administered.

Secondary outcome [1]

Cardiac Output measured the Edwards Lifesciences ClearSite Advanced haemodynamic monitor.

Timepoint [1]

1. Baseline just before administration of each intervention
2. During the 15 minute infusion period of each intervention
3. For 60 minutes after the infusions have been administered

Secondary outcome [2]

Cardiac Index measured the Edwards Lifesciences ClearSite Advanced haemodynamic monitor.

Timepoint [2]

1. Baseline just before administration of each intervention
2. During the 15 minute infusion period of each intervention
3. For 60 minutes after the infusions have been administered

Secondary outcome [3]

Stroke volume measured the Edwards Lifesciences ClearSite Advanced haemodynamic monitor.

Timepoint [3]

1. Baseline just before administration of each intervention
2. During the 15 minute infusion period of each intervention
3. For 60 minutes after the infusions have been administered

Secondary outcome [4]

Systemic vascular resistance measured the Edwards Lifesciences ClearSite Advanced haemodynamic monitor.

Timepoint [4]

1. Baseline just before administration of each intervention
2. During the 15 minute infusion period of each intervention
3. For 60 minutes after the infusions have been administered

Secondary outcome [5]

Plasma Osmolality using the a ABL 800 Laboratory Monitor

Timepoint [5]

1. Baseline just before administration of each intervention
2.Immediately after the 15 minute infusion period of each intervention
3. 60 minutes after the infusions have been administered

Eligibility

Key inclusion criteria

1. Adults (age >18 years but less than 60 years)
2. Healthy Volunteers
3. No regular medications

Minimum age

18 Years

Maximum age

60 Years

Sex

Both males and females

Can healthy volunteers participate?

Yes

Key exclusion criteria

Paracetamol use 24 hours prior to trial (in paracetamol only or in combination therapy)

Pregnancy

Chronic renal impairment (Creatinine >120 umol/L)

Chronic liver disease (ALT >100IU/L)

Morbid obesity (BMI >35kg/m2)

Known allergic reaction to IV paracetamol, mannitol or normal saline

Study design

Purpose of the study

Treatment

Allocation to intervention

Randomised controlled trial

Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)

Allocation will be concealment will be by means of sealed opaque envelopes. The sealed envelopes will be stored in a locked facility in the department of Anaesthesia at Austin Hospital, where the trial is being conducted. After informed participant consent has been obtained, an independent research assistant/investigator will open the sealed envelope which will contain the randomisation group.

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Simple randomisation using a computer software (i.e. computerised sequence generation) will be performed by the Principle Investigator. The computer will be password protected and located in the Department of Anaesthesia Research Facilities at Austin Hospital. Participants will be randomly allocated to one of the three infusion arms:

1. Paracetamol 1 gram (100 ml total volume)
2. Mannitol 3.9 grams (100 ml total volume)
3. Normal saline (0.9%) (100 ml total volume)

Masking / blinding

Blinded (masking used)

Who is / are masked / blinded?

The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data

Intervention assignment

Crossover

Other design features

NIL

Phase

Phase 4

Type of endpoint/s

Efficacy

Statistical methods / analysis

We will recruit 24 patients in total.

Sample size for the study will be calculated based on healthy volunteer database from our hospital. With a mean blood pressure of 120 mmHg, and a SD of 10 mmHg, if we were to demonstrate a mean difference between the groups of 10 mmHg, with an alpha level of 0.05, and beta value of 0.9, a total of 24 participants will be required.

Repeated measures analysis of variance modelling will be performed by fitting the main effects for treatment (i.e. paracetamol, mannitol, NS) and time and an interaction between treatment and time to determine if the 3 treatments behaved differently over time. Within each variable, analysis will be stratified by period (pre-infusion, infusion, observation) so there were 3 sets of analysis for each variable.

Because there will be 3 groups, the overall p-value for a group effect will simply answer the question "are these 3 groups significantly different from each other overall"; it will not inform us specifically where the differences are. For this information we will perform post-hoc analyses, looking for specific pairwise comparisons (paracetamol vs. mannitol, paracetamol vs. NS, mannitol vs. NS).

Modelling was performed using the PROC Mixed procedure in SAS version 9.2 (SAS Institute Inc., Cary, NC, USA). Mean and standard deviations for the three plasma osmolality levels will be calculated using the T-test function on Microsoft Excel software. Continuous data will be tested for normal distribution using the D’Agostino-Pearson omnibus test.

Recruitment

Recruitment status

Completed

Date of first participant enrolment

Anticipated

1/10/2013

Actual

2/10/2013

Date of last participant enrolment

Anticipated

1/04/2014

Actual

1/04/2014

Date of last data collection

Anticipated

Actual

Sample size

Target

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

VIC

Recruitment hospital [1]

Austin Health - Austin Hospital - Heidelberg

Recruitment postcode(s) [1]

3084 - Heidelberg

Funding & Sponsors

Funding source category [1]

Hospital

Name [1]

Austin Hospital

Address [1]

Department of Intensive Care
Studley Road, Heidelbeg, Victoria, 3084

Country [1]

Australia

Primary sponsor type

Hospital

Name

Austin Hospital

Address

Department of Intensive Care
Studley Road, Heidelbeg, Victoria, 3084

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Austin Health Research Ethics Unit

Ethics committee address [1]

Austin Health Research Ethics Unit
Austin Health
145 Studley Road
Heidelberg
Victoria, 3084

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

26/03/2013

Approval date [1]

06/06/2013

Ethics approval number [1]

H2013/05005

Summary

Brief summary

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

Trial website

NIL

Trial related presentations / publications

1. Chiam E, Weinberg L, Bellomo R. Haemodynamic effect of intravenous paracetamol in healthy Volunteers. European J Anaesthesiology 2015; 32 e-suppl 53: 15-16

2. Chiam L, Weinberg L, Bailey M, McNicol L, Bellomo R. Haemodynamic effect of intravenous paracetamol in healthy volunteers. A single centre blinded randomized controlled trial. Br J Clin Pharmacol 2015; Nov 25. doi: 10.1111/bcp.12841

Public notes

Contacts

Principal investigator

Name

A/Prof Laurence Weinberg

Address

Department of Anaesthesia Austin Hospital Studley Road Heidelberg, 3084, Victoria

Country

Australia

Phone

+61 3 94965000

Fax

+61 3 94596421

Laurence.Weinberg@austin.org.au

Contact person for public queries

Name

Laurence Weinberg

Address

Department of Anaesthesia Austin Hospital Studley Road Heidelberg, 3084, Victoria

Country

Australia

Phone

+61 3 94965000

Fax

+61 3 94596421

Laurence.Weinberg@austin.org.au

Contact person for scientific queries

Name

Laurence Weinberg

Address

Department of Anaesthesia Austin Hospital Studley Road Heidelberg, 3084, Victoria

Country

Australia

Phone

+61 3 94965000

Fax

+61 3 94596421

Laurence.Weinberg@austin.org.au

No information has been provided regarding IPD availability

What supporting documents are/will be available?

No Supporting Document Provided

Results publications and other study-related documents

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

Source	Title	Year of Publication	DOI
Embase	The haemodynamic effects of intravenous paracetamol (acetaminophen) in healthy volunteers: A double-blind, randomized, triple crossover trial.	2016	https://dx.doi.org/10.1111/bcp.12841

N.B. These documents automatically identified may not have been verified by the study sponsor.

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