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Trial registered on ANZCTR


Registration number
ACTRN12612000559819
Ethics application status
Approved
Date submitted
23/05/2012
Date registered
25/05/2012
Date last updated
15/01/2013
Type of registration
Retrospectively registered

Titles & IDs
Public title
Analgesic, Sedative and Antibiotic Pharmacokinetics during Extracorporeal Membrane Oxygenation: Understanding altered pharmacokinetics to improve patient outcomes.
Scientific title
Pharmacokinetic modelling of antibiotic, sedative and analgesic drugs and their relevant metabolites in critically ill patients receiving extracorporeal membrane oxygenation (ECMO) and development of dosing guidelines to optimise drug therapy during ECMO.
Secondary ID [1] 280313 0
Nil
Universal Trial Number (UTN)
U1111-1130-4355
Trial acronym
ASAP-ECMO
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Alterations to the pharmacokinetics of sedative and analgesic drugs and their metabolites (morphine - morphine 3 glucorunide, morphine 6 glucuronide, midazolam - 1 and 4 hydroxy midazolam, fentanyl - norfentanyl, dexmedetiomedine, propofol, thiopentone) in critically ill patients receiving ECMO. 286272 0
Alterations to the pharmacokinetics of broad spectrum antibiotics (ceftriaxone, cefepime, meropenem, gentamicin, ciprofloxacin, ticarcillin-clavulanate, piperacillin-tazobactum, vancomycin, linezolid, caspofungin, fluconazole, voriconazole, oseltamivir/oseltamivir carboxylate) in critically ill patients receiving ECMO. 286273 0
Condition category
Condition code
Cardiovascular 286500 286500 0 0
Other cardiovascular diseases
Respiratory 286501 286501 0 0
Other respiratory disorders / diseases
Anaesthesiology 286806 286806 0 0
Anaesthetics

Intervention/exposure
Study type
Observational
Patient registry
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
Patients will be eligible for recruitment any time during the ECMO run. Pharmacokinetic samples will be obtained as per the protocol when a new antibiotc ,sedative or analgesic drug is commenced or when an existing sedative or analgesic agent is discontinued by the treating clinician.

Sedative and analgesic drugs:
Sedative and analgesic drugs will be administered according to local policies at each ICU. As a guide, intravenous Infusions and boluses of morphine (10-30 mg/hr) and midazolam (10-30 mg/hr) titrated to a Richmond Agitation Sedation Scale (RASS) of -3 to -4 and a bispectral index (BIS) of 40-45. Patient ventilator interactions may also be used as a guide to titrate sedation especially in patients on venovenous ECMO. Therapeutic paralysis is at the discretion of the treating clinician and will be guided by neuromuscular monitoring.

Additional intravenous sedation if required may be provided with one of the following agents:

1. Propofol (10-200 mg/hr)
2. Dexmeditomedine (1 mcg/kg bolus and 0.1 -1.5 mcg/kg/min)
3. Fentanyl (50-300 mcg/hour) if morphine is discontinued for clinical reasons.
4. Thiopentone ( 100-200 mg/hour)*

* Note- Thiopentone is uncommonly used as an ultimate rescue sedative in some patients on ECMO

Antibiotics:
Antibiotic drug selection and dosing will be at the discretion of the clinician, based on the clinical context and unit guidelines. Doses will be reconstituted in 10 ml of diluent and given as bolus infusion in 50 ml over 30 minutes (except ciprofloxacin and vancomycin – 1-2 hour infusion), or as per local hospital protocols.


Sample collection
Blood samples will be drawn from an existing arterial line and collected in 2 ml tubes with Lithium Heparin anticoagulant. It is recommended that a closed loop Venous Arterial blood Management Protection system (VAMP, Edward Life sciences, Canada Inc) be used to minimise blood loss during sampling. Minimum sample volume is 2 mls per time point. Another 0.5 mls of blood will be drawn for each additional drug studied. It is unlikely for a patient to be receiving more than 4 study drugs at a given time during PK sampling. Labels and collection tubes will be provided.

Sedatives and analgesics:

General PK sampling

Blood samples will be taken from an existing arterial line at 0, 15, 30, 45, 60, 120, 180, 240, 360 minutes on commencement or cessation of a new sedative drug infusion. Details of drugs, doses and rates of administration to be documented on the data sheet.


Antibiotics:

All patients will be sampled over a single dosing period during ECMO treatment. Where two or more antibiotics of interest are prescribed for one patient, collect data on timing of administration for both drugs accurately and sample according to the antibiotic with the longer dosing interval. For example vancomycin 1g q12h and piperacillin 4.5g q6h; sample according to the vancomycin 12-hourly dosing schedule.

1. Six-hourly dosing schedule – Blood will be sampled from an existing arterial line at the following time points 0, 15, 30, 45, 60, 90, 120, 180 and 360 minutes.

2. Eight or 12-hourly dosing schedule – Blood samples will be collected from an existing arterial line at the following time points 0, 15, 30, 45, 60, 90, 120, 180 and 480 minutes.


Urine specimens:

Creatinine clearance for patients not receiving renal replacement therapy: An 8- hour urinary creatinine clearance collection will be obtained and assayed by the local pathology service to determine glomerular filtration rate. For patients receiving RRT the type and dose of the treatment will be documented on the data sheet.
Intervention code [1] 284797 0
Not applicable
Comparator / control treatment
Not applicable as this is an uncontrolled study.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 287063 0
Develop population PK models for antibiotic, sedative, analgesic and drugs and their relevant metabolites in critically ill patients receiving ECMO.
Timepoint [1] 287063 0
Following data anaylsis and interpretation- We have the power to detect relatively small changes within our small sample sizes because of the multiple observations per circuit/subject. Data from these studies will be analysed using non-linear mixed-effects models. This allows the estimation of typical population PK parameters and their inter- and intra-individual variability, plus the estimation of residual variability. We will fit random intercepts and slopes to allow for between patient differences in average responses and changes over time. Differential equations will be used to describe the population PK of study drugs and their metabolites expressed as PK parameters.
Primary outcome [2] 287064 0
Develop guidelines to optimise the dosing of sedative, analgesic and antibiotic drugs during ECMO.
Timepoint [2] 287064 0
Following data anaylsis and interpretation- The algorithms generated from PK analysis will form the basis for development of dosing guidelines that can be evaluated in later clinical studies. This knowledge is vitally important for optimising dosing schedules to maximise the opportunity for therapeutic success and minimise the risk for therapeutic failure. This will enable the clinicians to administer the " right dose of the right drug, at the right time during ECMO"
Secondary outcome [1] 297300 0
Improving sedation practices during ECMO
Timepoint [1] 297300 0
Following data anaylsis and interpretation-- The study will examine the uility of Richmond Agitation Sedation Scale (RASS) and bispectral index (BIS) in guiding sedtive and alagesic prescription during ECMO. This may inform the clinicians about the appropriate level of sedation in the complex group of patients.
Secondary outcome [2] 297556 0
Developement of ECMO specific sedation protocols
Timepoint [2] 297556 0
Following data anaylsis and interpretation-Using the right sedative agent at an appropriate dose may minimise ICU morbidity related to risk of infections, duration of mechanical ventilation and length of hospital stay, inotrope and vasopressor requirement, drug withdrawal, post traumatic stress etc. This not only has resource implications but significantly affects patient outcomes. Pharmacokinetic modelling of sedative and analgesic agents will identify drugs and thier doses that are most suitable for sedation during ECMO. This study will also examine the uitility of bispectral index (BIS) monitoring and clinical sedation scores to objectively titrate sedation and analgesia during ECMO. This information will then be used to deveop ECMO specific sedation protocols.

Eligibility
Key inclusion criteria
- Currently undergoing ECMO for respiratory +/- cardiac dysfunction
- Clinical indication for the antibiotics ceftriaxone, cefepime, meropenem, gentamicin, ciprofloxacin, ticarcillin-clavulanate, piperacillin-tazobactum, vancomycin, linezolid, caspofungin, fluconazole, voriconazole and oseltamivir
- Clinical indication for the sedatives and analgesics morphine, fentanyl, midazolam, dexmedetomidine, propfol or thiopentone
Minimum age
18 Years
Maximum age
89 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- No valid consent
- Known allergy to study drug
- Pregnancy
- S. Bilirubin >150
- Ongoing massive blood loss and blood product transfusion
- Therapeutic plasma exchange in the last 24 hours.

Study design
Purpose
Natural history
Duration
Cross-sectional
Selection
Defined population
Timing
Prospective
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment hospital [1] 415 0
The Prince Charles Hospital - Chermside
Recruitment hospital [2] 416 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment hospital [3] 417 0
The Alfred - Prahran
Recruitment outside Australia
Country [1] 3945 0
New Zealand
State/province [1] 3945 0
Auckland

Funding & Sponsors
Funding source category [1] 285303 0
Charities/Societies/Foundations
Name [1] 285303 0
Critical Care Research Group
Address [1] 285303 0
Adult Intensive Care Services
The Prince Charles Hospital
Rode Road
Chermside
Queensland 4032
Country [1] 285303 0
Australia
Funding source category [2] 286554 0
Charities/Societies/Foundations
Name [2] 286554 0
The Prince Charles Hospital Foundation
Address [2] 286554 0
Level 1 Admin Building, 627 Rode Road, Chermside, QLD, 4032, Australia
Country [2] 286554 0
Australia
Funding source category [3] 286555 0
Charities/Societies/Foundations
Name [3] 286555 0
Intensive Care Foundation
Address [3] 286555 0
Level 2, 10 Ievers Terrace
Carlton, Victoria 3053, Australia
Country [3] 286555 0
Australia
Funding source category [4] 286556 0
Charities/Societies/Foundations
Name [4] 286556 0
Australian and New Zealand College of Anaesthetists
Address [4] 286556 0
ANZCA House
630 St Kilda Road
Melbourne Vic 3004
Country [4] 286556 0
Australia
Funding source category [5] 286557 0
Charities/Societies/Foundations
Name [5] 286557 0
The Society of Hospital Pharmacists of Australia

Address [5] 286557 0
Suite 3, 65 Oxford Street
Collingwood, Victoria 3066 Australia
Country [5] 286557 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Critical Care Research Group
Address
Adult Intensive Care Services
The Prince Charles Hospital
Rode Road
Chermside
Queensland 4032
Country
Australia
Secondary sponsor category [1] 284109 0
None
Name [1] 284109 0
Address [1] 284109 0
Country [1] 284109 0
Other collaborator category [1] 260727 0
Hospital
Name [1] 260727 0
The Alfred Hospital
Address [1] 260727 0
PO Box 315
Prahran
Victoria 3181
Country [1] 260727 0
Australia
Other collaborator category [2] 260728 0
Hospital
Name [2] 260728 0
St Vincent's Hospital
Address [2] 260728 0
390 Victoria Street
Darlinghurst
NSW 2010
Country [2] 260728 0
Australia
Other collaborator category [3] 260729 0
Hospital
Name [3] 260729 0
Auckland City Hospital
Address [3] 260729 0
2 Park Road
Grafton
Auckland 1023
Country [3] 260729 0
New Zealand
Other collaborator category [4] 260730 0
Other Collaborative groups
Name [4] 260730 0
Burns Trauma and Critical Care Research Centre
Address [4] 260730 0
Royal Brisbane and Womens Hospital
The University of Queensland
Butterfield Street
Herston
Queensland 4029
Australia
Country [4] 260730 0
Australia
Other collaborator category [5] 260819 0
Other Collaborative groups
Name [5] 260819 0
TetraQ , Centre for Integrated Preclinical Drug Development
Address [5] 260819 0
Level 3, Steele Building
Staffhouse Road
The University of Queensland
Brisbane Queensland 4072
Country [5] 260819 0
Australia
Other collaborator category [6] 260820 0
Hospital
Name [6] 260820 0
Princess Alexandra Hospital
Address [6] 260820 0
199 Ipswich Road
Woolloongabba
Queensland 4102
Country [6] 260820 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 287246 0
Human Research Ethics Committee The Prince Charles Hospital
Ethics committee address [1] 287246 0
Administration Building, Lower Ground Floor
Rode Road
Chermside Queensland 4032
Ethics committee country [1] 287246 0
Australia
Date submitted for ethics approval [1] 287246 0
Approval date [1] 287246 0
04/11/2011
Ethics approval number [1] 287246 0
HREC/11/QPCH/121

Summary
Brief summary
Critically ill patients may be temporarily placed on extracorporeal memebrane oxygenation (ECMO) machines to allow the heart and lungs to rest while the disease is treated with drugs. ECMO, together with severe illness, affects the way drugs work. This research aims to understand the combined effects of the ECMO circuit and severe illness on drug treatment. The results will allow us to develop guidelines to assist doctors in administering the right dose of the right drug at the right time to patients on ECMO.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 33369 0
Dr Kiran Shekar
Address 33369 0
Critical Care Research Group Adult Intensive Care Services The Prince Charles Hospital Rode Road Chermside Qld 4032
Country 33369 0
Australia
Phone 33369 0
+61731394000
Fax 33369 0
+61731396120
Email 33369 0
kiran_shekar@health.qld.gov.au
Contact person for public queries
Name 16616 0
Dr Dr Kiran Shekar
Address 16616 0
Critical Care Research Group
Adult Intensive Care Services
The Prince Charles Hospital
Rode Road
Chermside Qld 4032
Country 16616 0
Australia
Phone 16616 0
+61 7 3139 5922
Fax 16616 0
Email 16616 0
kiran_shekar@health.qld.gov.au
Contact person for scientific queries
Name 7544 0
Dr Dr Kiran Shekar
Address 7544 0
Critical Care Research Group
Adult Intensive Care Services
The Prince Charles Hospital
Rode Road
Chermside Qld 4032
Country 7544 0
Australia
Phone 7544 0
+61 7 3139 4000
Fax 7544 0
Email 7544 0
kiran_shekar@health.qld.gov.au

No data has been provided for results reporting
Summary results
Not applicable