Combined Rehabilitation and Nutritional Support vs. Standard Care in In-Hospital Endocarditis Treatment (ENDOCARE)

Combined Physical Rehabilitation and Individualized Nutritional Support Versus Standard of Care During In-hospital Endocarditis Treatment

Infective endocarditis (IE) is associated with high morbidity and mortality. Patients with IE are affected by a lengthy hospitalization, leading to physical deconditioning and a rapid decline in physical fitness, muscle mass and strength. Moreover, prolonged antibiotic regimens frequently result in nausea, antibiotic-associated diarrhea and Clostridioides difficile (C.difficile) intestinal infections that further negatively affect patient health. These physical challenges are further exacerbated by the negative impact on mental health, increasing the overall burden of the illness. Implementing a targeted rehabilitative strategy in the hospital setting may therefore improve patient care including physical health and overall quality of life during hospitalization.

Study Overview

• Status: Terminated
• Conditions: Bacteremia; Cardiac Rehabilitation; Physical Therapy; Infective Endocarditis; Endocarditis, Bacterial; Nutrition Intervention; Probiotic Intervention; Infection; Heart
• Intervention / Treatment: Dietary supplement: Probiotic treatment; Behavioral: Intensive physical Therapy; Behavioral: Individualised Nutritional Support; Other: Standard hospital care

Detailed Description

BACKGROUND:

Infective endocarditis (IE) is a severe infection of the heart's inner lining, typically the valves, carrying high risks of acute heart failure and death. Patients often face extended hospitalizations (up to six weeks or longer) for intravenous antibiotic treatments, with 30-50% requiring urgent valve surgery. The incidence of IE is 8-10 per 100,000 person-years and rising due to aging populations and increased use of cardiac implantable devices, accounting for 650-700 cases annually in Denmark. Without treatment, mortality is nearly 100%, and with treatment, it ranges from 5-30% during the initial hospitalization, influenced by factors such as infection site, causative agent, age, and comorbidities.

IE significantly impacts patients' health due to prolonged hospitalization. Many experience rapid physical decline, including reduced cardiorespiratory fitness, strength, and overall fitness, caused by bed rest, malnutrition, and limited activity. Recovery is often difficult, with worsening physical, mental, and emotional states. The POET trial found poor self-rated health triples mortality risk. Up to 35% of patients do not return to work, and 65% face readmission within a year. Long hospital stays also increase the need for nursing home care.

Malnutrition is common in IE patients, raising risks of death, illness, and impairment. Acute illness amplifies nutritional deficits, worsening muscle wasting and overall health. The EFFORT trial showed early nutritional support reduces mortality and complications, yet no randomized studies have addressed nutrition in IE patients.

Intravenous antibiotics add distress, often causing nausea, diarrhea, and C. difficile infections. Probiotics like S. boulardii show promise in preventing these side effects.

Cardiac rehabilitation has proven benefits for other heart conditions, improving exercise capacity, quality of life, and reducing readmissions. However, evidence is limited for in-hospital IE rehabilitation. Tailored, supervised programs during hospitalization could address physical and mental health needs, improving overall recovery and quality of life.

PRIMARY AIM:

To investigate the effectiveness of individualized physical rehabilitation and nutritional support designed to reduce physical deconditioning and prevent treatment-related harms thus ultimately improving mental health in patients hospitalized with endocarditis.

HYPOTHESES:

Within a 2-by-2 factorial design, a patient-centered, individualized, and adaptable physical rehabilitation and nutritional plan during lengthy hospitalization will improve mental health more than standard care.

Furthermore, in the same factorial framework, a probiotic supplement during antibiotic-treatment will decrease the rate of antibiotic-associated diarrhea compared to no probiotic supplement.

NUTRITIONAL SUPPORT:

In the intervention group, nutritional screening and support begin within 24 hours of randomization. Individualized nutritional plans are developed based on the NRS 2002 protocol and 2018 international guidelines. A dietitian sets energy requirements using the weight-adjusted Harris-Benedict equation and establishes protein intake targets between 1.2-1.5 g/kg of body weight, adjusting to 0.8 g/kg for patients with acute renal failure.

Patients are screened for risk of refeeding syndrome with routine blood tests, including magnesium, phosphate, and other relevant biomarkers (e.g., bilirubin, creatinine, albumin, electrolytes, etc.). The initial dietary plan includes hospital-provided meals, snacks from an "à la carte" menu, and oral nutritional supplements (ONS). Daily food records monitor intake, and if patients fail to meet 75% of caloric and protein targets for three consecutive days-or earlier based on clinical judgment-escalation to enteral tube feeding or parenteral feeding is initiated.

INDIVIDUALLY PLANNED PHYSICAL EXERCISE BY AN INTERDISCIPLINARY TEAM LEAD BY A SPECIALIZED REHABILITATION PHYSIOTHERAPIST:

The ENDOCARE team, consisting of a cardiologist, nurse, and physiotherapist, optionally involving a family member, will meet with the patient the first weekday after inclusion to design a personalized exercise regimen. This regimen accounts for comorbidities, performance status, disease severity, and support resources. Weekly meetings with the team will address patient concerns and ensure optimal care.

Exercise Modalities

Patients will participate in Intensive Exercise to reduce deconditioning and enhance well-being, focusing on:

Progressive Resistance Exercise: Major muscle groups (e.g., leg presses, arm rows, arm pushes) are targeted with 2-3 sessions/week, using stationary equipment or elastic bands. Training follows a linear progression (3 sets per exercise starting at 15 ± 2 RM, progressing to 10 ± 2 RM) and integrates principles like range of motion and time under tension.

Cardiovascular Exercise: Sessions involve 20 minutes of moderate-intensity exercise (Borg RPE 12-14) 3-4 times/week, using arm ergometers or stationary beds. Intensity and structure (continuous or interval) are adjusted based on patient preference.

Physical Activity Daily physical activity, guided by Danish recommendations (10,000 steps/day), is encouraged using a gradual progression model (e.g., PACE-UP). Activity monitoring is supported by SENS motion accelerometers, with data transferred to a smartphone app. Depending on funding, tablets may provide real-time feedback on activity levels near patient beds.

Control Group Patients in the control group receive standard hospital care, including an initial physiotherapist assessment and 1-2 supervised or self-managed exercise sessions per week.

Risks Potential risks include musculoskeletal injuries (e.g., strains, sprains), fatigue, and overtraining.

GUIDE FOR PROBIOTIC ADMINISTRATION:

In the intervention group, S. boulardii treatment begins at inclusion. Patients will receive Sacchaflor capsules (Pharmaforce Aps), containing S. boulardii (5×10^9 DBVPG 6763 strain) and mannan oligosaccharide (MOS), a supplement derived from Saccharomyces cerevisiae. The capsules are administered twice daily until the end of antibiotic treatment. If the patient is discharged with continued antibiotics, S. boulardii will be used for up to 30 more days.

In the control group, no probiotics will be given for 30 days post inclusion.

Possible side effects include gastrointestinal disturbances (e.g., flatulence, bloating, constipation) and, rarely, fungemia or allergic reactions).

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Denmark
  • Hvidovre, Denmark, 2650
    • Hvidovre Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

INCLUSION CRITERIA

• Clinical diagnosis of left-sided (native, prosthetic, or culture-negative) bacterial infective endocarditis mandating iv antibiotic treatment, including Cardiac Implantable Electronic Devices infections, irrespective of cause and location as defined by the ESC modified Duke Criteria
• Age ≥ 18 years

EXCLUSION CRITERIA

• Hemodynamic instability (defined as a systolic blood pressure <90 mmHg and lactate >2.2 mmol/l measured in an arterial blood gas.
• Expected to be discharged within 3 days
• Immunocompromised due to severe combined immunodeficiency, HIV, or hematological malignancy
• Fungal endocarditis
• Pregnancy
• Unwilling or unable to sign or understand informed consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Integrated Physical Therapy and Nutritional Support with Probiotic Saccharomyces boulardii; Intensive physical therapy + individualised nutritional support + administration of probiotic yeast saccharomyces boulardii	Dietary supplement: Probiotic treatment; Administration of probiotic yeast Saccharomyces boulardii twice daily; Behavioral: Intensive physical Therapy; Tailored exercise programs supervised by trained physiotherapists, focusing on improving cardiorespiratory fitness, strength, and functional capacity.; Behavioral: Individualised Nutritional Support; Personalized nutritional plans guided by a dietitian, addressing malnutrition and caloric/protein deficiencies with daily caloric intake adjustments and supplements if necessary based on the EFFORT trial.
Active Comparator: A combined Intensive physical Therapy and individualised Nutritional Support intervention; Intensive physical Therapy + Individualised Nutritional Support	Behavioral: Intensive physical Therapy; Tailored exercise programs supervised by trained physiotherapists, focusing on improving cardiorespiratory fitness, strength, and functional capacity.; Behavioral: Individualised Nutritional Support; Personalized nutritional plans guided by a dietitian, addressing malnutrition and caloric/protein deficiencies with daily caloric intake adjustments and supplements if necessary based on the EFFORT trial.
Active Comparator: Administration of probiotic yeast Saccharomyces boulardii	Dietary supplement: Probiotic treatment; Administration of probiotic yeast Saccharomyces boulardii twice daily
Placebo Comparator: Control group; Standard hospital care	Other: Standard hospital care; Patients will receive standard hospital care

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mental health (MH) measured by the standardized Short Form 36 (SF-36)	Mental Component Summary (MCS) of the Medical Outcome Study Short Form 36 version 2 (SF-36) which has been validated in Danish and in cardiac populations and is widely used in controlled clinical trials. Scores range from 0 to 100, with higher scores indicating better-perceived health	30 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
All-cause mortality		30 days
Days alive and out of hospital		30 day in hospital, and 90 day out-of-hospital
Change in number of sit and stand in 30 seconds from baseline to 14 days	Sit and stand test	14 days
Quality of life from EQ-5D	Quality of life measured efte 30 days using EuroQol-5 Domain (EQ-5D) The EQ VAS records the patient's self-rated health on a vertical visual analogue scale, where the endpoints are labelled 'The best health you can imagine' and 'The worst health you can imagine'. The VAS can be used as a quantitative measure of health outcome that reflect the patient's own judgement.	14, 30, and 90 days follow-up
Days alive without diarrhea	Assessment with Bristol Stool Chart	30 days in hospital and 90 days out of hospital

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
The occurrence of C. difficile infection	Defined as an episode of diarrhea combined with the detection of toxins A or B, or both, from a rectal swap	14 days and 30 days
SENS motion	Number of daily steps	First 7 days
Albumin Measurement	Blood test	14 days
NT-proBNP	Blood test	14 days after admission
Left ventricular ejection fraction	Left ventricular ejection fraction measured with echocardiography	14 days
Self-rated Hospital Anxiety and Depression Scale (HAD)	The HADS questionnaire has seven items each for depression and anxiety subscales. Scoring for each item ranges from zero to three, with three denoting highest anxiety or depression level. A total subscale score of >8 points out of a possible 21 denotes considerable symptoms of anxiety or depressio	14, 30, and 90 days follow-up
HbA1c	Blood test	Day 14
Lipids	Blood test	Day 14
Number of patients at risk of malnutrition		Day 14
Number of patients getting daily average of at least 75% of the caloric and protein targets on day 4		Day 14
Number of patients required for enteral tube feeding or parenteral feeding		Day 14
Grip strength		14, 30, and 90 days

Collaborators and Investigators

• Sponsor: Johannes Grand
• Investigators: Principal Investigator: Johannes Grand, MD, PhD, Copenhagen University Hospital Amager-Hvidovre, Department of Cardiology

Study record dates

Study Major Dates

• Study Start (Actual): February 19, 2025
• Primary Completion (Actual): December 7, 2025
• Study Completion (Actual): December 7, 2025

Study Registration Dates

• First Submitted: August 19, 2024
• First Submitted That Met QC Criteria: August 19, 2024
• First Posted (Actual): August 21, 2024

Study Record Updates

• Last Update Posted (Actual): December 15, 2025
• Last Update Submitted That Met QC Criteria: December 7, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: Physical Therapy; Cardiac rehabilitation; Infective endocarditis; Endocarditis team; Individualized Nutritional Support; Probiotic yeast Saccharomyces Boulardii
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Pathologic Processes; Heart Diseases; Sepsis; Systemic Inflammatory Response Syndrome; Inflammation; Bacterial Infections; Bacterial Infections and Mycoses; Cardiovascular Infections; Pathological Conditions, Signs and Symptoms; Bacteremia; Endocarditis; Infections; Endocarditis, Bacterial
• Other Study ID Numbers: ENDOCARE-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data that underlie the results reported in the publication will be shared. Data will be available beginning after publicatoin of the main papers. Access will be granted to researchers who provide a methodologically sound proposal, which will be reviewed by the national governing body for approval both regarding ethics and patients data safety.
• IPD Sharing Time Frame: 1/1 2028 - 31/12 2037
• IPD Sharing Access Criteria: Access will be granted to researchers who provide a methodologically sound proposal. All data avaiable will potentially be shared if approved be athorities. Data transfer can be made through an approoved data transfar system, which should be made available by the researcher seeking the data.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No