'Cardiac and Intramuscular Adaptations Following Short-term Exercise Prehabilitation in Unfit Patients Scheduled to Undergo Hepatic- or Pancreatic Surgery' (CIRCULATE)

Surgery remains an important treatment modality in the treatment of hepatopancreatobiliary (HPB) malignancies, but the physiological stress caused by surgery is at the same time a challenge for the homeostasis of patients. A patient's preoperative aerobic capacity has been found to have a consistent relation with postoperative outcomes in major abdominal surgery, with low aerobic capacity being associated with a higher risk of postoperative morbidity and mortality. Preoperative exercise prehabilitation programs can effectively increase the ability of patients to cope with surgical-induced allostatic load, by improving aerobic capacity, and functioning of the respiratory, cardiovascular, and/or musculoskeletal systems. However, besides the effect of exercise prehabilitation on physical fitness in terms of improvement of aerobic capacity as measured by the cardiopulmonary exercise test (CPET), the exact role of adaptations in cardiac and/or skeletal muscle function contributing to the improvement in aerobic capacity is still unknown. Insight in the physiological adaptations that lead to improvement in aerobic capacity after prehabilitation in patients with low aerobic capacity will enable caregivers to individually optimize the exercise program (e.g. by changing exercise frequency, intensity, duration and type) and better explain the rationale and effectiveness behind the short-term physical exercise training program to patients. Therefore, the main objective of this study is to assess the central (cardiac function) and peripheral (skeletal muscle function) physiological adaptations in response to short-term exercise prehabilitation. Secondary objective is to assess the relationship between immune function and exercise. In this study, unfit patients are asked to undergo additional in-magnet exercise testing to investigate the central and peripheral physiological adaptations in response to exercise prehabilitation.

Study Overview

• Status: Not yet recruiting
• Conditions: Surgery; Perioperative Care; Prehabilitation; Exercise Prehabilitation
• Intervention / Treatment: Diagnostic test: exercise MRI

Detailed Description

Rationale: Surgery remains an important treatment modality in the treatment of hepatopancreatobiliary (HPB) malignancies, but the physiological stress caused by surgery is at the same time a challenge for the homeostasis of patients. A patient's preoperative aerobic capacity has been found to have a consistent relation with postoperative outcomes in major abdominal surgery, with low aerobic capacity being associated with a higher risk of postoperative morbidity and mortality. Preoperative exercise prehabilitation programs can effectively increase the ability of patients to cope with surgical-induced allostatic load, by improving aerobic capacity, and functioning of the respiratory, cardiovascular, and/or musculoskeletal systems. However, besides the effect of exercise prehabilitation on physical fitness in terms of improvement of aerobic capacity as measured by the cardiopulmonary exercise test (CPET), the exact role of adaptations in cardiac and/or skeletal muscle function contributing to the improvement in aerobic capacity is still unknown. Insight in the physiological adaptations that lead to improvement in aerobic capacity after prehabilitation in patients with low aerobic capacity will enable caregivers to individually optimize the exercise program (e.g. by changing exercise frequency, intensity, duration and type) and better explain the rationale and effectiveness behind the short-term physical exercise training program to patients.

Objective: The main objective is to assess the central (cardiac function) and peripheral (skeletal muscle function) physiological adaptations in response to short-term exercise prehabilitation. Secondary objective is to assess the relationship between immune function and exercise.

Study design: This study is a single-center prospective clinical trial with a one-group pretest-posttest design. It will take place at the University Medical Center Groningen (UMCG), the Netherlands. As part of standard care, all patients scheduled to undergo hepatic or pancreatic surgery for (suspected) HPB malignancies at the UMCG are screened for low aerobic capacity, and subjected to exercise prehabilitation in case of low aerobic capacity. In this study, unfit patients are asked to undergo additional in-magnet exercise testing to investigate the central and peripheral physiological adaptations in response to exercise prehabilitation.

Study population: Unfit patients diagnosed with a (suspected) HPB malignancy who are scheduled to undergo elective hepatic or pancreatic surgical resection and participate in the exercise prehabilitation program. Intervention: In-magnet exercise test consisting of in vivo exercise cardiac magnetic resonance (exCMR) imaging and 31P-magnetic resonance spectroscopy (31P-MRS) during exercise testing in a MR-compatible ergometer, before and after the 4-week prehabilitation program. In addition to exCMR imaging and 31P-MRS during rest, blood will be withdrawn at three different time points (before first CPET, after first CPET and before second CPET).

Main study parameters/endpoints: The difference in left and right ventricular function will be measured by exCMR in rest, during progressive exercise, and recovery to assess the effect of the preoperative physical exercise training program on cardiac function. The difference in quadriceps phosphocreatine concentration (PCr), quadriceps inorganic phosphorus concentration (Pi), and quadriceps pH at rest, during progressive exercise, and recovery rate will be measured by 31P-MRS to assess the effect of the prehabilitation program on skeletal muscle function. Differences in inflammatory and immunological cytokines and chemokines before the first CPET, directly after the first CPET and before second CPET.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: The intervention consists of four extra hospital visits. During these visits the in-magnet exercise tests and blood sample collection (exCMR and 31P-MRS) will be performed. The in-magnet exercise test can lead to physical discomfort, due to an uncomfortable feeling while cycling on an ergometer whilst laying supine in the MRI. However, before the in-magnet exercise test, a CPET in a controlled environment (continuous 12-lead electrocardiography registration and under supervision of a sports physician) is performed and therefore the in-magnet exercise test can be safely performed when the CPET does not show contra-indications for exercise. The imaging consisting of exCMR and 31P-MRS has previously been shown to be safe and is already widely used in different studies at the UMCG. Patients are not exposed to any radiation and/or contrast agents. The blood samples that will be taken are not expected to cause an extra risk/burden to the patients. Except for little pain/discomfort, or the possibility of local hemorrhage which can easily solved by compression of the vein

• Study Type: Interventional
• Enrollment (Anticipated): 12
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Netherlands
  • Groningen, Netherlands, 9713GZ
    • University Medical Center Groningen
    • Contact: Joost M Klaase, Prof. dr.; Email: j.m.klaase@umcg.nl
    • Sub-Investigator: Allard G. Wijma, Drs.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• VO2 at the VAT ≤13 ml/kg/min and/or VO2peak ≤18 ml/kg/min, as determined during the baseline CPET;
• More than 18 years of age;
• Scheduled for elective liver- or pancreatic resection at the UMCG;
• Willing to participate in the home-based bimodal prehabilitation program;
• Has given consent to participate in the study.

Exclusion Criteria:

• Patients requiring acute (emergency) surgery;
• Patients not capable of cycling on a cycle ergometer;
• Patients with contraindications to physical exercise training;
• Patients receiving neoadjuvant chemotherapy
• Contraindications for exCMR (e.g., claustrophobia, implanted cardiac devices)
• Atrial fibrillation or other significant arrhythmia during the CPET;
• Body weight >140 kg;
• Body height >190 cm;
• History of myocardial infarction, percutaneous coronary intervention or coronary artery bypass graft <3 months or untreated severe obstructive coronary artery stenosis;
• More than moderate left-sided valve disease;
• Complex congenital heart disease.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Imaging arm; Participants are subjected to in-magnet exercise test consisting of in vivo exercise cardiac magnetic resonance (exCMR) imaging and 31P-magnetic resonance spectroscopy (31P-MRS) during exercise testing in a MR-compatible ergometer, before and after the 4-week prehabilitation program.

Diagnostic test: exercise MRI; All patients are subjected to two types of in-magnet exercise tests consisting of exercise cardiac magnetic resonance imaging (exCMR) and Phosphorus 31 magnetic resonance spectrography (31P MRS) of the quadriceps muscle, during exercise at various exercise intensities in a supine position using a MR-compatible ergometer (Lode MR Ergometer Pedal, Lode BV, Groningen, the Netherlands).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Central physiological adaptations	Central adjustments will be determined by differences in LV/RV diastolic strain rate, LV and RV volumes, slope of early LV/RV filling, left and right atrial reservoir strain and emptying fraction, pulmonary artery distensibility and pulsatility, and cardiac output measurements using exCMR, before and after the prehabilitation program.	through study completion, an average of 1 year
Peripheral physiological adaptations	Peripheral adjustments will be determined by differences in quadriceps PCr, Pi and pH at rest and during progressive exercise and post-exercise recovery rates of quadriceps PCr, Pi and pH using 31P MRS, before and after the prehabilitation program.	through study completion, an average of 1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Postoperative outcomes	Secondary outcomes are perioperative and postoperative outcomes. Postoperative outcomes include overall postoperative complications within 30 days after surgery, grade of complication according to the Clavien-Dindo classification 36 , length of hospital stay in days after surgery, mortality within 30 days after surgery, and readmissions within 30 days after discharge.	through study completion, an average of 1 year

Collaborators and Investigators

• Sponsor: University Medical Center Groningen
• Collaborators: Nationaal Fonds tegen Kanker

Study record dates

Study Major Dates

• Study Start (Anticipated): April 1, 2023
• Primary Completion (Anticipated): April 1, 2024
• Study Completion (Anticipated): June 1, 2024

Study Registration Dates

• First Submitted: February 10, 2023
• First Submitted That Met QC Criteria: March 6, 2023
• First Posted (Actual): March 16, 2023

Study Record Updates

• Last Update Posted (Actual): March 16, 2023
• Last Update Submitted That Met QC Criteria: March 6, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Other Study ID Numbers: NL83611.042.23

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No