Symptoms and General Pathology

All Conditions

Heart and Blood Diseases

Substance Related Disorders

Wounds and Injuries

Ischemia

Cardiotoxicity

Reperfusion Injury

Myocardial Reperfusion Injury

Heart Diseases

Drug-Related Side Effects and Adverse Reactions

Chemically-Induced Disorders

Radiation Injuries

Remote ischaemic conditioning in the form of a blood pressure cuff on upper arm inflated upto 200 mm Hg (or systolic BP + 20 mm Hg if low platelets e.g. 50-150 x10\^9/L, skip remote ischaemic conditioning (RIC) if platelets \< 50 x 10\^9/L) for 5 minutes, then deflated to 0 mm Hg for 5 minutes, for 4 cycles before beginning of chemotherapy infusion. The entire pre-conditioning phase will last 40 minutes.

Blood pressure cuff on upper arm inflated to 10 mm Hg for 5 minutes, then deflated to 0 mm Hg for 5 minutes, for 4 cycles before beginning of chemotherapy infusion. The entire control comparator will last 40 minutes

each cycle of Remote Ischaemic Conditioning (RIC) consists of inflating a blood pressure cuff on the upper limb (arm) upto 200mm Hg (systolic BP + 20 mm Hg for low platelets, e.g. 50-150 x 10\^9/L; skip RIC if platelets \< 50 x 10\^9/L) for 5 minutes, then deflated to 0 mm Hg for 5 minutes.

Remote Ischaemic Conditioning

Sham control blood pressure cuff placement at 10 mm Hg for 5 minutes, then deflated to 0 mm Hg for 5 minutes.

Placebo

Robin Chung, MBBS MRCP

Michael Mallouppas, MBBS MRCP

Michael Mallouppas, MRCP

Derek M Yellon, DSc FACC FAHA

Malcolm Walker, MD FRCP

Alison Macklin, BSc

Derek M Yellon, PhD FACC FAHA

Alison Macklin

Cancer survival has improved steadily due to earlier detection and treatment. Despite the established efficacy of anthracycline chemotherapy, its damaging effects on the heart (cardiotoxicity) limits treatment and confers acute and long term adverse cardiovascular consequences. Protective strategies for the heart (cardioprotection) with iron binders (chelation), heart rate (beta blockade) and blood pressure (renin angiotensin inhibition) medications have demonstrated promise in adult cancer patients, but these treatments are typically prescribed only after significant changes in heart chamber size and pumping ability are detected by imaging investigations (myocardial dysfunction).

Furthermore, these conventional therapies are constrained by important side effects that affect bone marrow, blood pressure, and the kidneys.

Remote ischaemic conditioning (RIC) protects the heart by activating cell survival pathways through brief repeated inflations and deflations of a blood pressure cuff to limit blood flow temporarily (noninjurious ischaemia). These innate survival mechanisms prevent part of the cellular injury that occurs during the ischaemia reperfusion cascade during a heart attack (myocardial infarction). Ischaemia reperfusion injury also shares common biochemical pathways with anthracycline cardiotoxicity, and thus RIC may be a novel form of nonpharmacological cardioprotection that can be applied when undergoing anthracycline chemotherapy.

The investigators propose a pilot single centre randomised controlled trial to investigate the effect of RIC on reducing heart muscle damage (myocardial injury) in anthracycline-treated cancer patients. The investigators will assess subclinical myocardial injury using high-sensitivity blood tests (troponin T levels) and advanced imaging techniques, monitor heart rhythm disturbances (cardiac arrhythmia) and analyse metabolic changes in urine and blood during chemotherapy, at specified time points, and follow up to 5 years after completing chemotherapy treatment).

This pilot study aims to demonstrate whether remote ischaemic preconditioning (RIC), delivered as a nonpharmacological treatment via repeated inflations and deflations of a limb blood pressure cuff, can reduce subclinical myocardial injury from anthracycline chemotherapy. Chemotherapy cardiotoxicity is the dose limiting constraint in anthracycline chemotherapy regimens, and conventional drug treatments to prevent and treat it are limited by important interactions with blood pressure, kidney function or bone marrow function. The lifetime cancer risk is between 1 in 2 and 1 in 3 in the general population. Cancer treatment and survival has improved steadily 50% of patients now survive their initial cancer diagnosis, but approximately 25 to 50% of survivors will have abnormal cardiac function over the next twenty years. Historically, anthracycline chemotherapy dosing has been stratified to limit the incidence of clinical heart failure to around 5%. More recent studies have reported at least one third of anthracycline chemotherapy patients demonstrate a significant rise in Troponin levels as a blood biomarker of subclinical myocardial injury as well as documented evidence of biomarker rise even after a single cycle of chemotherapy, and thus the absolute threshold for myocardial injury may be lower and thus more prevalent than these conservative figures.

In standard dosing regimens, chemotherapy may be delayed or suspended in cancer patients based on the simplified measure of ejection fraction (EF) as a measure of cardiac systolic function. Conventional heart failure treatments such as betablockers or ACE inhibitors are usually prescribed only after a significant fall in EF, even though myocardial injury occurs long before this imprecise measurement changes. RIC has been shown to reduce myocardial injury and improve outcomes in elective and emergency percutaneous coronary intervention (PCI) and elective coronary artery bypass graft surgery (CABG). The common biochemical pathways in ischaemia reperfusion and anthracycline-induced cardiac myocyte injury suggest that RIC may be an unexplored nonpharmacological treatment to reduce myocardial injury for cancer patients.

This pilot study aims to demonstrate the effectiveness of RIC as an elegant noninvasive, nonmedicinal treatment to reduce myocardial injury in cancer patients, and therefore poses no significant ethical issues. RIC is known to be a safe intervention with no known significant adverse effects. Some patients have reported mild discomfort during cuff inflation. A small number have experienced minor skin bruising at the cuff site which is transient. There are no known long term adverse effects of RIC,

Recruitment Patients will be identified by their usual oncology team, and referred to the cardiology team based solely on known inclusion and exclusion criteria, which will ensure this process is free from undue influence.

The benefits of the study include an increase in the scientific understanding of how RIC may lead to a reduction in myocardial injury, as well as longitudinal documentation of myocardial injury in the form of blood biomarkers, ECG changes, metabolic changes, and novel imaging markers in cancer patients undergoing a common form of chemotherapy.

Effect of Remote Ischaemic Conditioning in Oncology Patients

A Single Centre Double-blinded Randomized Placebo Controlled Pilot Study Investigating the Effect of Remote Ischaemic preConditioning in ONCology Patients Undergoing Chemotherapy (ERIC-ONC)

Biomarker of myocardial injury using high-sensitivity Troponin-T for above time points as serial measurements.

Major Adverse Cardiovascular Event (myocardial infarction, clinical heart failure requiring admission, life-threatening arrhythmia atrioventricular (AV) block requiring pacemaker, cardiac or cancer death)

Echocardiographic longitudinal function (GLS %)

two weeks ambulatory electrocardiographic (ECG) monitoring for atrial fibrillation, supraventricular tachycardia, ventricular tachycardia, atrioventricular block

for heart failure / raised left atrial pressure

Comparison of changes in micro ribonucleic acid (miRNA) and mitochondrial deoxyribonucleic acid (mtDNA), markers of protein expression at baseline (before) and at 3-months' follow up after completing chemotherapy regimen

University College London Hospitals

University College, London

Neoplasms

Digestive System Diseases

Nervous System Diseases

Behaviors and Mental Disorders

Death

Carcinoma

Carcinoma, Hepatocellular

Liver Failure

Hepatic Insufficiency

Brain Death

Liver Diseases

Gastrointestinal Diseases

Adenocarcinoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Liver Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Brain Diseases

Central Nervous System Diseases

Coma

Unconsciousness

Consciousness Disorders

Neurobehavioral Manifestations

Neurologic Manifestations

Central Nervous System Depressants

All Drugs and Chemicals

Hematinics

Anesthetics

Liver Extracts

Participants will receive RIC during transplant and the initial four post-transplant days. During transplant: first intervention after induction of anesthesia but before commencing surgery and the second at the conclusion of the procedure. After transplant: RIC applied daily during the first four consecutive postoperative days. Pneumatic tourniquet will be used to induce RIC

Each RIC intervention will comprise three cycles of 5 minutes of inflation followed by 5 minutes of deflation of a pneumatic tourniquet placed in mid-thigh.

Remote Ischemic Conditioning (RIC)

Portable Tourniquet System(PTSii, Delfi Medical Innovations, Inc.) used to perform RIC interventions.

Pneumatic tourniquet

Baburao Koneru, MD, MPH

This study will assess the feasibility of lower limb-ischemia induced Remote Ischemic Conditioning (RIC) in the perioperative period before, during, and after Orthotopic Liver Transplantation (OLT). Remote ischemic conditioning will consist of 3 cycles of 5 minutes of lower limb ischemia induced via a mid-thigh pneumatic tourniquet, followed by 5 minutes of reperfusion. Interventions will take place after anesthesia induction but before surgery, at the completion of the procedure, and on the mornings of post-operative days 1-4.

Orthotopic liver transplantation (OLT) is associated with a very high risk of complications. In a recent multi-center study of 450 patients, 79% had at least one complication and 63% had severe (Clavien-Dindo grade III or higher) complications. The number and severity of complications are associated with death within 30 days, hospital length of stay, graft and patient survival. Infections are the most common group of complications, followed by pulmonary, renal and liver graft dysfunction. Interventions that decrease these complications after OLT are likely to improve clinical outcomes.

Remote ischemic conditioning is an innate biological phenomenon wherein a brief single or repetitive ischemic stimulus in an organ or tissue such as skeletal muscle induce protection in remote/distant organs against ischemia and other noxious stimuli. This effect can be induced by inflating a pneumatic tourniquet on a leg or arm for a few minutes (usually 5-10) and subsequently deflating to allow reperfusion. This process is usually repeated 3-4 times to ensure an adequate dose of the conditioning stimulus. The conditioning stimulus could be applied before (Preconditioning), concurrent with (Perconditioning), or soon after the index noxious/ischemic insult (Postconditioning).

The goal of this study is to assess the feasibility, patient acceptance, and safety of RIC in liver recipients. In addition, the investigators will obtain data on posttransplant complications. Information obtained from this study will help guide the design of a future randomized, controlled trial to test the benefit of RIC in liver recipients.

Remote Ischemic Conditioning (RIC) in Recipients of Brain Death Donor Livers - A Feasibility and Safety Study

Proportion of enrolled liver recipients that complete all 6 remote ischemic conditioning (RIC) interventions.

Median intervention-related pain score during each of the post-operative interventions, in extubated patients who are able to communicate. Using the Numerical Rating Scale (NRS, Ferrieira-Valente MA PAIN Volume 152, 2011), patients were asked to rate their pain following the intervention on a scale of 0-10 with 0 being no pain experienced to 10 as the maximum pain felt.

- Withdrawal of consent due to discomfort/pain in the lower extremity

Percentage of participants who developed Early Allograft Dysfunction (EAD) which is defined as:

* Aspartate Transaminase (AST) or Alanine Transaminase (ALT)\> 2,000 U/L at any point within the first seven post-transplant days, or
* Total Bilirubin (TB) \> 10 mg/dL on postoperative day 7,or
* International Normalized Ratio (INR)\> 1.6 on postoperative day 7.

Percentage of Participants who developed Prolonged Respiratory Insufficiency (PRI) defined as:

* Ventilator support for \>2 postoperative days after transplant, or
* Reintubation after extubation, within 7 days of transplant. Patients who require brief re-intubation for an endoscopic, radiologic, or surgical procedure would not be considered to have PRI if they are extubated within 2 days of the end of the procedure.

Percentage of participants who developed Acute Kidney Injury (AKI)

Based on Kidney Disease - Improving Global Outcomes (KDIGO) criteria, AKI criteria are:

Stage 2:

- 2.0-2.9 fold rise in serum creatinine from baseline

Stage 3:

* \> 3.0 fold rise in serum creatinine from baseline, or
* Serum creatinine of \> 4.0 mg/dL, with an acute (\<48 hours) increase of 0.3 mg/dL in serum creatinine or subacute (\< 7 days) increase in serum creatinine of 0.5 mg/dL, or
* Initiation of renal replacement therapy.

In patients who are receiving dialysis pre-op, time to discontinuation of dialysis, if occurring within 90 days of transplantation.

Percentage of patients with Clavien-Dindo \>/= grade III b complications (Dindo D, Demartines N, Clavien P, Annals of Surgery 2004).

The Clavien-Dindo Complications grade ranges from Grade I (Any deviation from the normal postoperative course without the need for pharmacological treatment or surgical, endoscopic and radiological interventions Allowed therapeutic regimens are: drugs as antiemetics, antipyretics, analgetics, diuretics and electrolytes and physiotherapy. This grade also includes wound infections opened at the bedside) to Grade V (Death). Grade IIIb would be any intervention requiring general anesthesia.

In patients with Clavien-Dindo \>/= IIIb complications, number of such complications per patient.

Number of days in ICU post-transplant. Starting at post-op day 0 and ending on the calendar date that the patient is transferred out of ICU, dies, or post-op day 90, whichever is soonest.

Number of days in hospital post-transplant. Starting at post-op day 0 and ending on the calendar date that the patient is leaves the hospital, dies, or post-op day 90, whichever is soonest.

Percentage of patients with functioning allograft at 90 days post-transplant

Percentage of patients alive at 90 days post-transplant

Number of subjects that received fewer than 6 interventions,.

Rutgers, The State University of New Jersey

Professor, Department of Surgery

In addition to the clinical.trials. gov definitions, adverse events will be monitored related to the RIC intervention:

Withdrawal of consent due to discomfort/pain in the lower extremity. Any other adverse event considered by the primary clinical team to be related to the RIC intervention.

Participants will receive RIC during transplant and the initial four post-transplant days. During transplant: first intervention after induction of anesthesia but before commencing surgery and the second at the conclusion of the procedure. After transplant: RIC applied daily during the first four consecutive postoperative days. Pneumatic tourniquet will be used to induce RIC

Remote Ischemic Conditioning (RIC): Each RIC intervention will comprise three cycles of 5 minutes of inflation followed by 5 minutes of deflation of a pneumatic tourniquet placed in mid-thigh.

Pneumatic tourniquet: Portable Tourniquet System(PTSii, Delfi Medical Innovations, Inc.) used to perform RIC interventions.

Remote Ischemic Conditioning (RIC) Group

Subjects in this cohort were chosen via retrospective record review, and selected applying the same inclusion and exclusion criteria as in the RIC cohort. They were chosen consecutively in revere-chronological order that began at the start of the study date. Target ratio of RIC:Controls was 1:2. No matching was performed for age, sex, and model for end stage liver disease (MELD) score.

Historical Control Cohort

Subjects received remote ischemic conditioning

Remote Ischemic Conditioning (RIC) Cohort

Historical control subjects received liver transplants in an earlier period

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

United States

Region of Enrollment

Two modifications resulted in a smaller number of subjects. Number of cycles, the duration of each cycle and the number of postoperative interventions were not addressed. Lack of randomization led to historical cohort to evaluate some outcomes.

Participants enrolled to receive RIC during transplant and the initial four post-transplant days and who receive all 6 RIC interventions.Subjects in historical control cohort chosen as described above

Percentage of Participants Completing Entire Intervention Protocol

Unintubated subjects were asked to rate intervention-related pain on a scale from 0-10 for each of the postoperative interventions. The maximum pain score obtained from each subject was recorded and the median score for all subjects was calculated. Scale range from 0 - 10 with 10 indicating highest sensation of pain.

Intervention-related Pain Score

Participants who withdrew consent due to pain from RIC intervention.

Withdrawal of Consent Due to Pain

Denominator for this and other postoperative outcomes except death and complications was 30 due to the exclusion of subject who died prior to transplantation

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Effect of Remote Ischaemic Conditioning in Oncology Patients	NCT02471885	Cardiotoxicity	Remote Ischaemi... Placebo	16 Years - 80 Years	University College, London
Remote Ischemic Conditioning (RIC) in Recipients of Brain Death Donor Livers - A Feasibility and Safety Study	NCT02635347	Liver Failure Carcinoma, Hepa...	Remote Ischemic... Pneumatic tourn...	18 Years -	Rutgers, The State University of New Jersey

Spots Global Cancer Trial Database for remote ischemic conditioning