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Trial registered on ANZCTR
Registration number
ACTRN12615001099516
Ethics application status
Approved
Date submitted
24/09/2015
Date registered
19/10/2015
Date last updated
5/02/2016
Type of registration
Retrospectively registered
Titles & IDs
Public title
Haemodynamic Effect of Intravenous Paracetamol during and after Cardiac Surgery
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Scientific title
Haemodynamic Effect of Intravenous Paracetamol during and after Cardiac Surgery
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Secondary ID [1]
282277
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Nil
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Universal Trial Number (UTN)
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Cardiopulmonary bypass
288813
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Cardiac surgery
288814
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Condition category
Condition code
Anaesthesiology
289170
289170
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0
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Anaesthetics
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Surgery
289173
289173
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0
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Surgical techniques
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Cardiovascular
296628
296628
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0
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Coronary heart disease
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Intravenous paracetamol (Actavis, North Adelaide, SA)
Paracetamol is one of the most commonly used medications in the world. The intravenous format is the preferred method of administration in the intraoperative and immediate postoperative periods.
In 100mL of solution for infusion, intravenous paracetamol contains the following:
Paracetamol = 1g
Mannitol = 3.91g
Cysteine hydrochloride monohydrate
Dibasic dihydrate sodium phosphate
Sodium hydroxide
Hydrochloric acid
Water for injections
The insertion of a pulmonary artery catheter (PAC) is required for routine anaesthesia treatment during cardiac surgery. Haemodynamic measurements will be monitored via the PAC. After insertion of the PAC, 100mL paracetamol (containing 1g paracetamol and 3.91g mannitol) will be administered intravenously.
Volume of paracetamol to be administered:
Actavis (North Adelaide, SA) recommends 1g of paracetamol per administration with a maximum of 4g of paracetamol per day. The minimum dose interval is 4 hours. The duration of infusion is 15 minutes.
In this trial, a 1g of paracetamol will be administered every 6 hours, for 3 consecutive doses, which is in line with the manufacturer's recommendations. The first dose will be administered on arrival to the operating room, prior to induction of anaesthesia. The second dose will be administered 6 hours after the first, which may be near completion of surgery or in the intensive care unit. The final dose will be 6 hours later in the intensive care unit. The duration of each infusion will be set at 15 minutes.
Paracetamol will be administered in addition to standard care analgesia. In accordance with strict hospital protocols, all doses of paracetamol administered will be recorded or logged on the participants analgesic chart.
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Intervention code [1]
286907
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Treatment: Drugs
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Comparator / control treatment
Normal saline 0.9% is an intravenous fluid solution that provides maintenance and replacement of deficits of extracellular fluid. It is commonly used throughout the world as an infusion proving water for hydration for patients undergoing major surgery.
For this clinical trial 100 ml Normal Saline 0.9% will be administered every 6 hours over a 15 minute period, for 3 consecutive doses. The first dose will be administered on arrival to the operating room, prior to induction of anaesthesia. The second dose will be administered 6 hours after the first, which may be near completion of surgery or in the intensive care unit. The final dose will be 6 hours later in the intensive care unit. The duration of each infusion will be set at 15 minutes.
In accordance with strict hospital protocols, all doses of saline administered will be recorded or logged on the participants fluid balance chart.
All patients will also receive standard postoperative analgesia.
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Control group
Placebo
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Outcomes
Primary outcome [1]
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The primary outcome is a composite outcome using pressure based haemodynamic variables, namely systolic blood pressure, diastolic blood pressure, mean arterial blood pressure. These will be recorded from a arterial line inserted as part of standard care that measure continuous systolic blood pressure, diastolic blood pressure, and mean arterial blood pressure.
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Assessment method [1]
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Timepoint [1]
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The primary outcome will be measures at the following peri-operative timepoints using the measurements from the arterial line.
1. Baseline (BL) just after pulmonary artery catheter insertion
2. 5 minutes (T5)
3. 10 minutes (T10)
4. 15 minutes (T15)
5. 30 minutes (T30)
6. Pre-cardiopulmonary bypass
7. Rewarming
8. ICU arrival (ICU 1)
9. ICU 6 hours (ICU 6)
10. ICU 12 hours (ICU 12)
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Secondary outcome [1]
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Cardiac output will be measured by a bolus thermodilution technique using a Swan-Ganz pulmonary artery catheter
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Assessment method [1]
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Timepoint [1]
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The secondary outcome will be measured at the following peri-operative timepoints using the measurements from the Swan-Ganz pulmonary artery catheter:
1. Baseline (BL) just after pulmonary artery catheter insertion
2. 5 minutes (T5)
3. 10 minutes (T10)
4. 15 minutes (T15)
5. 30 minutes (T30)
6. Pre-cardiopulmonary bypass
7. Rewarming
8. ICU arrival (ICU 1)
9. ICU 6 hours (ICU 6)
10. ICU 12 hours (ICU 12)
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Secondary outcome [2]
302170
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Cardiac index will be measured by a bolus thermodilution technique using a Swan-Ganz pulmonary artery catheter
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Assessment method [2]
302170
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Timepoint [2]
302170
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The secondary outcome will be measured at the following peri-operative timepoints using the measurements from the Swan-Ganz pulmonary artery catheter:
1. Baseline (BL) just after pulmonary artery catheter insertion
2. 5 minutes (T5)
3. 10 minutes (T10)
4. 15 minutes (T15)
5. 30 minutes (T30)
6. Pre-cardiopulmonary bypass
7. Rewarming
8. ICU arrival (ICU 1)
9. ICU 6 hours (ICU 6)
10. ICU 12 hours (ICU 12)
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Secondary outcome [3]
302171
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Plasma paracetamol levels
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Assessment method [3]
302171
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Timepoint [3]
302171
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Plasma paracetamol levels will be measured at the following peri-operative timepoints:
1. Baseline (BL) just after pulmonary artery catheter insertion
2. 5 minutes (T5)
3. 10 minutes (T10)
4. 15 minutes (T15)
5. 30 minutes (T30)
6. Pre-cardiopulmonary bypass
7. Rewarming
8. ICU arrival (ICU 1)
9. ICU 6 hours (ICU 6)
10. ICU 12 hours (ICU 12)
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Secondary outcome [4]
302172
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Composite secondary end point of renal biomarkers, which will include including serum and urine NGAL and cystatin C. These renal biomarkers are sensitive indicators of renal injury and inflammation.
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Assessment method [4]
302172
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Timepoint [4]
302172
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Serum and urine NGAL and cystatin C levels will be measured at the following peri-operative timepoints:
1. Baseline (BL) just after pulmonary artery catheter insertion
2. 5 minutes (T5)
3. 10 minutes (T10)
4. 15 minutes (T15)
5. 30 minutes (T30)
6. Pre-cardiopulmonary bypass
7. Rewarming
8. ICU arrival (ICU 1)
9. ICU 6 hours (ICU 6)
10. ICU 12 hours (ICU 12)
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Secondary outcome [5]
302173
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Plasma (blood) levels of Pro-inflammatory effects using TNF-a, IL-6 and IL-10.
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Assessment method [5]
302173
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Timepoint [5]
302173
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Plasma levels of TNF-a, IL-6 and IL-10 will be measured at the following peri-operative timepoints:
1. Baseline (BL) just after pulmonary artery catheter insertion
2. 5 minutes (T5)
3. 10 minutes (T10)
4. 15 minutes (T15)
5. 30 minutes (T30)
6. Pre-cardiopulmonary bypass
7. Rewarming
8. ICU arrival (ICU 1)
9. ICU 6 hours (ICU 6)
10. ICU 12 hours (ICU 12)
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Secondary outcome [6]
302174
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Core body temperature will be measure via an electronic nasal probe temperature transducer that will be inserted 8-10cm into the nasopharyngeal area.
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Assessment method [6]
302174
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Timepoint [6]
302174
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Core body temperature will be measured at the following peri-operative timepoints:
1. Baseline (BL) just after pulmonary artery catheter insertion
2. 5 minutes (T5)
3. 10 minutes (T10)
4. 15 minutes (T15)
5. 30 minutes (T30)
6. Pre-cardiopulmonary bypass
7. Rewarming
8. ICU arrival (ICU 1)
9. ICU 6 hours (ICU 6)
10. ICU 12 hours (ICU 12)
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Secondary outcome [7]
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Time to first postoperative request for opioid treatment, which will be assessed by review of the medical records.
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Assessment method [7]
302175
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Timepoint [7]
302175
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This timepoint will commence at the completion of surgery until the first request for opioid treatment.
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Secondary outcome [8]
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Amount of opioid adminstered during stay in ICU, which will be assessed by review of the medical records.
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Assessment method [8]
302176
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Timepoint [8]
302176
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This timepoint will commence at the completion of surgery until the end of ICU stay.
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Secondary outcome [9]
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Frequency of inotrope use, which will be assessed by review of the medical records.
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Assessment method [9]
302177
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Timepoint [9]
302177
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This timepoint will commence at the completion of surgery until the end of ICU stay.
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Secondary outcome [10]
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Amount of fluids used, which will be assessed by review of the medical records.
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Assessment method [10]
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Timepoint [10]
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This timepoint will commence at the completion of surgery until the end of ICU stay.
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Secondary outcome [11]
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Type of surgery
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Assessment method [11]
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Timepoint [11]
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This will be collected from the medical records.
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Secondary outcome [12]
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Total volume of administered CPB prime fluids will be collected from the perfusion medical records.
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Assessment method [12]
317935
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Timepoint [12]
317935
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Duration of cardiopulmonary bypass which will commences when full cardiopulmonary bypass flows are established and concludes once the patient has separated from bypass and spontaneous circulation has been achieved.
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Secondary outcome [13]
317936
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Baseline EuroSCORE
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Assessment method [13]
317936
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Timepoint [13]
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This will be collected from the medical records.
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Secondary outcome [14]
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Baseline Parsonnet indices.
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Assessment method [14]
317937
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Timepoint [14]
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This will be collected form the medical records.
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Secondary outcome [15]
317938
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Duration of ICU stay.
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Assessment method [15]
317938
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Timepoint [15]
317938
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This will be collected form the medical records.
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Secondary outcome [16]
317939
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Duration of hospital stay.
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Assessment method [16]
317939
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Timepoint [16]
317939
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This will be collected from the medical records.
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Secondary outcome [17]
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Renal failure assessed using the international RIFLE criteria for Acute Kidney injury
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Assessment method [17]
317940
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Timepoint [17]
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Duration of hospital stay
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Secondary outcome [18]
318145
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Pneumonia that will be assessed using the international criteria of raised white cell count in addition to focal changes on an x-ray.
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Assessment method [18]
318145
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Timepoint [18]
318145
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Duration of hospital stay
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Eligibility
Key inclusion criteria
1. Adult surgery patients (age >18 years)
2. Cardiac surgery requiring cardiopulmonary bypass
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Minimum age
18
Years
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Maximum age
No limit
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key exclusion criteria
Paracetamol use 24 hours prior to surgery (in paracetamol only or in combination therapy)
Pregnancy
Chronic renal impairment (creatinine >250 umol/L)
Chronic liver disease (ALT >200IU/L)
Morbid obesity (BMI >35kg/m2)
Known allergic reaction to IV paracetamol
Consumption of caffeine (e.g. coffee or energy drinks), consumed within 10 hours of surgery
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Study design
Purpose of the study
Prevention
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Allocation to intervention
Randomised controlled trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
All patients undergoing cardiac surgery are evaluated preoperatively at the cardiac surgery and anaesthesia
pre-admissions clinic at least 4 weeks prior to surgery. Patients will be identified for study entry by the
investigators or an anaesthetist or research co-ordinator acting on behalf of the principle investigators by
surveillance of patients in the pre-admissions clinic.
Allocation concealment will be by sealed opaque envelopes.
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participants will be randomly assigned to one of two groups using a computer generated
random number allocation system with permuted blocks prior to the commencement of the
study.
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Masking / blinding
Blinded (masking used)
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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
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 4
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Type of endpoint/s
Pharmacokinetics
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Statistical methods / analysis
We will recruit 50 patients in total, 25 patients in the paracetamol group and 25 patients in the control group. This is in keeping with realistic power calculations used in other studies evaluating the haemodynamic effects of IV paracetamol in patients undergoing major surgery.
Sample size for the study was calculated based on our pilot data evaluating patients undergoing cardiac surgery at Austin hospital. With an average blood pressure of 120mmHg, and a SD of 10 mmHg, if we were to demonstrate a mean difference between the paracetamol group and control group of 10mmHg, with a power value of 80%, we require a minimum of 18 patients to be recruited into each group. We will therefore recruit 25 patients in each arm, a total of 50 patients.
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Recruitment
Recruitment status
Completed
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Date of first participant enrolment
Anticipated
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Actual
7/06/2013
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Date of last participant enrolment
Anticipated
3/11/2014
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Actual
19/11/2014
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Date of last data collection
Anticipated
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Actual
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Sample size
Target
50
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Accrual to date
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Final
50
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Recruitment in Australia
Recruitment state(s)
VIC
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Recruitment hospital [1]
857
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Austin Health - Austin Hospital - Heidelberg
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Recruitment postcode(s) [1]
6671
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3084 - Heidelberg
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Funding & Sponsors
Funding source category [1]
287054
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Hospital
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Name [1]
287054
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Austin Hospital
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Address [1]
287054
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Department of Intensive Care
15, Studley Road, Heidelberg, Victoria, 3084
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Country [1]
287054
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Australia
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Primary sponsor type
Hospital
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Name
Austin Hospital
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Address
Department of Intensive Care
15 Studley Road, Heidelberg, Victoria, 3084
Australia
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Country
Australia
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Secondary sponsor category [1]
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None
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Name [1]
285836
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Address [1]
285836
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Country [1]
285836
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Ethics approval
Ethics application status
Approved
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Ethics committee name [1]
289083
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Austin Health Research Ethics Unit
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Ethics committee address [1]
289083
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Austin Health Research Ethics Unit
Austin Health
145 Studley Road
Heidelberg
Victoria, 3084
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Ethics committee country [1]
289083
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Australia
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Date submitted for ethics approval [1]
289083
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26/03/2013
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Approval date [1]
289083
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06/06/2013
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Ethics approval number [1]
289083
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H2013/05006
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Summary
Brief summary
There are currently no double-blinded, randomised controlled trials that assess the haemodynamic effects of paracetamol in patients undergoing cardiac surgery. The effects of cardiopulmonary bypass (CPB) on paracetamol pharmacokinetic are also poorly understood.
This study will add to a growing body of evidence evaluating the safety and efficacy of paracetamol use in patients undergoing cardiac surgery.
Hypothesis: Paracetamol (1g IV) has adverse effects on blood pressure in patients undergoing cardiac surgery.
No of patients: 50
No of recruiting hospitals: 1
Randomisation: Patients will be randomised in a 1:1 fashion via a computer generated randomisation program to either paracetamol IV formulation (N=25) or control treatment (normal saline 0.9%) (N=25).
Blinding: This is a double-blinded clinical trial. Surgical teams, intraoperative and postoperative nursing staff, and patients will be blinded to assignment of treatment.
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Trial website
Nil
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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A/Prof Laurence Weinberg
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Address
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Department of Anaesthesia Austin Hospital, 15 Studley Road Heidelberg, 3084, Victoria
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Country
39118
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Australia
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Phone
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+61 3 94965000
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Fax
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+61 3 94596421
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Email
39118
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[email protected]
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Contact person for public queries
Name
39119
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A/Prof Laurence Weinberg
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Address
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Department of Anaesthesia Austin Hospital, 15 Studley Road Heidelberg, 3084, Victoria
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Country
39119
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Australia
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Phone
39119
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+61 3 94965000
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Fax
39119
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+61 3 94596421
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Email
39119
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[email protected]
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Contact person for scientific queries
Name
39120
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A/Prof Laurence Weinberg
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Address
39120
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Department of Anaesthesia Austin Hospital, 15 Studley Road Heidelberg, 3084, Victoria
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Country
39120
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Australia
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Phone
39120
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+61 3 94965000
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Fax
39120
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+61 3 94596421
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Email
39120
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[email protected]
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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 hemodynamic effects of intravenous paracetamol (acetaminophen) vs normal saline in cardiac surgery patients: A single center placebo controlled randomized study.
2018
https://dx.doi.org/10.1371/journal.pone.0195931
N.B. These documents automatically identified may not have been verified by the study sponsor.
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