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Trial registered on ANZCTR

Registration number

ACTRN12610000496011

Ethics application status

Approved

Date submitted

15/06/2010

Date registered

16/06/2010

Date last updated

16/06/2010

Type of registration

Prospectively registered

Titles & IDs

Public title

A non-invasive way to protect against the stress of surgery for heart disease

Scientific title

The protective effect of remote ischaemic preconditioning in congenital heart disease patients undergoing cardiopulmonary bypass surgery

Secondary ID [1]

Nil

Universal Trial Number (UTN)

Trial acronym

Linked study record

Health condition

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

Cardiopulmonary by-pass surgery-associated ischemia-reperfusion stress in paediatric patients with congenital heart disease.

Condition category

Condition code

Cardiovascular

Diseases of the vasculature and circulation including the lymphatic system

Surgery

Surgical techniques

Human Genetics and Inherited Disorders

Other human genetics and inherited disorders

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Remote Ischemic Preconditioning (RIPC) will be instituted by four 5-minute cycles of leg ischemia with intervening 5 minutes of reperfusion immediately following induction of standard anaesthesia in the operating room. A standard WelchAllen blood pressure cuff is placed on the mid-to upper thigh of the leg which is free of intravenous (i.v.)/arterial lines. Inflating the blood pressure cuff to a pressure exceeding the patient’s systolic pressure by 30 mmHg will constrict the site to interrupt local blood flow and thus perfusion of the lower leg (i.e. if systolic pressure is 70mmHg then the cuff will be inflated to 100mmHg). The cuff would be deflated to permit reperfusion. Blood flow interruption and restoration will be monitored by standard pulse-oxymetry. RIPC is performed after the patient has been anesthetised while routine central lines are being placed.

Intervention code [1]

Treatment: Other

Comparator / control treatment

Control (Placebo) patients will have sham placement of cuff without inflation.

Control group

Placebo

Outcomes

Primary outcome [1]

The identification of whether the molecular signalling response (proteome and intracellular signal transduction) in blood (plasma and lymphocyte mitochondria) and cardiac mitochondria (resected tissue) that normally occurs in patients undergoing congenital heart surgery with cardiopulmonary by-pass support is altered by RIPC-treatment (highly regulated, non-invasively-induced, localised leg ischaemia (5min) and reperfusion (5min) for 4 cycles) before surgery.

Timepoint [1]

Blood samples collected at baseline, and post-operatively at 3, 6, 12, 24 hours . Myocardial resected tissue, intraoperatively.

Secondary outcome [1]

The total doses of inotropic, chronotropic, and afterload reducing agents.

Timepoint [1]

Post-operatively at 3, 6, 12, 24 hours .

Secondary outcome [2]

Arterial blood gases measured from blood samples by blood gas machine.

Timepoint [2]

Blood samples collected at baseline, and post-operatively at 3, 6, 12, 24 hours .

Secondary outcome [3]

Mean systemic arterial, and right atrial pressures via in-line catheters and pressure transducers.

Timepoint [3]

3, 6, 12, and 24 hours after aortic cross clamp release.

Secondary outcome [4]

Serum glucose measured by hospital pathology biochemical assay.

Timepoint [4]

Blood samples collected at baseline, and post-operatively at 3, 6, 12, 24 hours.

Secondary outcome [5]

Post-operative serum electrolytes measured by hospital pathology biochemical assays.

Timepoint [5]

Blood samples collected at baseline, and post-operatively at 3, 6, 12, 24 hours

Secondary outcome [6]

Post-operative serum arterial lactate measured by hospital pathology biochemical assay.

Timepoint [6]

Blood samples collected at baseline, and post-operatively at 3, 6, 12, 24 hours.

Secondary outcome [7]

Post-operative blood urea nitrogen measured by hospital pathology biochemical assay.

Timepoint [7]

Blood samples collected at baseline, and post-operatively at 3, 6, 12, 24 hours.

Secondary outcome [8]

Post-operative creatinine measured by hospital pathology biochemical assay.

Timepoint [8]

Blood samples collected at baseline, and post-operatively at 3, 6, 12, 24 hours.

Secondary outcome [9]

Post-operative fluid balance (i.e. recorded total volume and type of fluid intake, urine output, and chest tube drainage).

Timepoint [9]

Daily from day of operation until discharge from hospital (generally after 10-12 days).

Secondary outcome [10]

Ventilator rates and pressures recorded for estimates of lung function and compliance.

Timepoint [10]

From day of operation until extubation of ventilation.

Secondary outcome [11]

Post-operative total hours of mechanical respirator ventilation required.

Timepoint [11]

The tally of hours from day of operation until extubation of ventilation.

Secondary outcome [12]

The number of days in the cardiac intensive care unit and the hospital are recorded.

Timepoint [12]

Daily from day of operation until discharge from hospital (generally after 10-12 days).

Secondary outcome [13]

The total number of days in hospital.

Timepoint [13]

Daily from day of operation until discharge from hospital (generally after 10-12 days).

Eligibility

Key inclusion criteria

Patients with tetralogy of Fallot having surgery for the first time.

Minimum age

1 Months

Maximum age

18 Years

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

Patients with chromosomal defects, associated congenital lung malformations and haematological disorders

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)

The implementer of the RIPC or Sham control/placebo treatment protocols will open one sealed envelope in numerical order immediately prior to placement of the blood pressure cuff and they will apply the RIPC treatment or sham control protocol accordingly.

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

Random allocation is made in blocks in order to keep the sizes of the 2 treatment groups similar. Due to the expected relative uniformity of condition in the patient group and the small number of subjects the design will not be stratified. The randomisation will be performed in secret by a member from Heart Research (not involved in working for the trial) using SPSS statistical software generated randomisation and will place each designation sequentially in numbered envelopes 1 to 40, for patient 1 to 40 and the envelopes will be signed and sealed.

Masking / blinding

Blinded (masking used)

Who is / are masked / blinded?

Intervention assignment

Parallel

Other design features

Phase

Not Applicable

Type of endpoint/s

Efficacy

Statistical methods / analysis

Recruitment

Recruitment status

Not yet recruiting

Date of first participant enrolment

Anticipated

5/07/2010

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)

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

National Health and Medical Research Council (NHMRC)

Address [1]

Level 1
16 Marcus Clarke Street
Canberra ACT 2601

Country [1]

Australia

Primary sponsor type

Individual

Name

Professor Igor Konstantinov

Address

Department of Cardiac Surgery
Royal Children's Hospital
Flemington Road, Parkville, VIC 3052

Country

Australia

Secondary sponsor category [1]

Individual

Name [1]

Dr Michael Cheung

Address [1]

Department of Cardiology
Royal Children's Hospital
Flemington Road, Parkville, VIC 3052

Country [1]

Australia

Secondary sponsor category [2]

Individual

Name [2]

Dr Salvatore Pepe

Address [2]

Heart Research,
Murdoch Children's Research Institute
Royal Children's Hospital
Flemington Road, Parkville, VIC 3052

Country [2]

Australia

Secondary sponsor category [3]

Individual

Name [3]

Dr Vera Ignjatovic

Address [3]

Haemotology Research,
Murdoch Children's Research Institute
Royal Children's Hospital
Flemington Road, Parkville, VIC 3052

Country [3]

Australia

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Royal Children's Hospital Human Ethics Committee

Ethics committee address [1]

Royal Children's Hospital
Flemington Road
Parkville, VIC 3052

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

Approval date [1]

26/03/2010

Ethics approval number [1]

29133

Summary

Brief summary

Lay Summary:
Support of the blood circulation during heart surgery using the heart-lung bypass machine is inevitably associated with organ damage and associated reduced function. This is due to reduced blood flow (ischemia), the effects of restoration of flow (reperfusion injury) and the subsequent inflammation that is caused. The body has its own way of protecting itself against reduced blood flow and oxygen by a mechanism known as preconditioning. In essence, brief periods of mild ischemia are protective against a subsequent more severe episode of ischemia. These periods of mild ischemia can be of the organ itself or of another organ in the body. For example ischemia of the leg can protect the heart against ischemia, so called “remote preconditioning”.  We have shown in animal and human models that remote preconditioning using a tourniquet (or blood pressure cuff) placed around a thigh for brief periods (similar in duration to when taking blood samples from children) reduces the amount of injury to heart muscle by 50% and also leads to improved heart and lung function. We have shown that remote preconditioning in a similar way protects the organs of a heterogeneous group of children undergoing cardiac surgery, resulting in better function of the heart and lungs and also a reduction of the inflammatory response to the heart-lung machine. This could potentially reduce the problems in looking after children after surgery and also reduce the amount of time spent in the intensive care unit. 
We will study paediatric patients undergoing heart surgery inorder to identify key protein and metabolic changes that occur within this 'heart-protection' protocol. All interventions will be performed during the period of routine general anaesthesia at the time of surgical repair. We will study the degree of organ injury induced by heart-lung bypass using standard intensive care parameters and equipment for measuring lung function. The degree of plasma and blood cell metabolic function will be assessed by laboratory tests. Blood samples will be taken from indwelling catheters routinely placed at the time of surgery and not require additional venepuncture. Measurements will be made prior to surgery and also at set time intervals in the first 24 hours postoperatively to determine the evolution of effects.

Primary Objective: 
Does remote ischemic preconditioning (RIPC) modify the global plasma proteomic and mitochondrial response in patients undergoing congenital heart surgery?   

Hypothesis: 
RIPC induces significant changes to global proteomic response in plasma and the metabolic function in heart muscle and lymphocyte mitochondria of patients undergoing congenital heart surgery. 

Aims:
To assess in blood plasma and lymphocyte/myocardial mitochondria the impact of RIPC on the global proteomic and mitochondrial metabolic function response to heart surgery with cardiopulmonary bypass support.

Secondary Objectives:
Does RIPC modify clinical markers of injury and cardiopulmonary function post-Cardiopulmonary bypass in patients undergoing congenital heart surgery?   

Hypothesis: 
Remote IPC reduces post-cardiopulmonary bypass  release of markers of cellular injury and permits recovery of cardiac pump function with less complication including inotrope requirement in patients undergoing congenital heart surgery. 

Aims:
To assess the impact of remote IPC on lactate release, inotrope requirement, and standard clinical cardiopulmonary assessments in response to heart surgery with cardiopulmonary bypass support.

This small randomised, blinded, surgical trial of preoperative therapy with highly regulated, brief, non-invasively-induced, localised leg ischaemia and reperfusion, will test for the capacity to invoke remote ischemic preconditioning-related molecular signalling (proteomic and metabolic) changes.  The study will recruit 40 paediatric tetralogy of patients to RIPC treatment or SHAM RIPC (Placebo control) treatment groups and is expected to be completed by the end of March 2012.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Address

Country

Phone

Fax

Contact person for public queries

Name

Professor Igor Konstantinov

Address

Department of Cardiac Surgery
Royal Childrens' Hospital
Flemington Road
Parkville, VIC, 3052

Country

Australia

Phone

+61 3 93455200

Fax

+61 3 93456386

Igor.Konstantinov@rch.org.au

Contact person for scientific queries

Name

Professor Igor Konstantinov

Address

Department of Cardiac Surgery
Royal Childrens' Hospital
Flemington Road
Parkville, VIC, 3052

Country

Australia

Phone

+61 3 93455200

Fax

+61 3 93456386

Igor.Konstantinov@rch.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	Remote Ischemic Preconditioning (RIPC) modifies the plasma proteome in children undergoing repair of tetralogy of fallot: A randomized controlled trial.	2015	https://dx.doi.org/10.1371/journal.pone.0122778

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

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