Precision Exercise Training for Sepsis

(PRECISE Trial)

Overseen By John Boyd, MD

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: University of British Columbia

Must not be taking: Immunomodulatory drugs

Disqualifiers: Diabetes, Autoimmune diseases, Hypertension, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 48

Duration: 12 weeks

32 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests a personalized exercise program for sepsis survivors to see if it improves their ability to exercise and boosts their immune system. The program includes tailored strength and aerobic exercises over a few months.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are on daily immunomodulatory drugs, you cannot participate in the trial.

What data supports the effectiveness of the treatment Precision Exercise Training for Sepsis?

Research suggests that exercise training can protect against organ dysfunction in sepsis, improve physical activity and muscle strength in survivors, and reduce mortality in patients with low muscle mass. Early exercise rehabilitation also helps improve functional recovery in severe sepsis patients. ^{1 2 3 4 5}

Is Precision Exercise Training generally safe for humans?

Research suggests that exercise training, including aerobic and resistance training, is generally safe for humans. High-intensity strength training may even be safer for the cardiovascular system than low-intensity training, as it causes fewer increases in blood pressure and cardiac output. ^{6 7 8 9 10}

How is Precision Exercise Training different from other treatments for sepsis?

Precision Exercise Training is unique because it involves individualized exercise plans that combine strength and aerobic exercises, which may help protect against organ damage in sepsis by improving fitness and modulating biological responses, unlike standard treatments that do not typically include exercise. ^{2 3 11 12 13}

Research Team

Graeme Koelwyn, PhD

Principal Investigator

University of British Columbia

Eligibility Criteria

This trial is for sepsis survivors over 19 years old with reduced cardiorespiratory fitness, who can commit to a 12-week exercise program. They must have had symptoms like fast breathing, confusion, or low blood pressure. It's not for those on oxygen therapy, recent heart events, uncontrolled conditions like diabetes or hypertension, pregnant women, or those unable to consent.

Inclusion Criteria

Signed informed consent

My heart and lung fitness is below 80% of what's expected for my age and sex.

≥60 days prior to study enrollment, known or suspected infection that includes at least two of the following clinical criteria that together constitute a new bedside clinical score termed quickSOFA (qSOFA): respiratory rate >22breaths/min, altered mentation, or systolic blood pressure <100mmHg

Exclusion Criteria

Desaturation during exercise SpO2<85%

Known pregnancy/ intending to get pregnant within 28 days of enrolling in the study or breastfeeding

Cardiovascular contraindication or musculoskeletal limitations to exercise as assessed during the cardiopulmonary exercise test

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants complete 12-weeks of precision exercise training consisting of individualized, nonlinear periodized strength and aerobic exercise training

12 weeks

36 sessions (in-person)

Attention Control

Participants in the control group receive usual care procedures and general lifestyle advice 1x per week

12 weeks

12 contacts (virtual)

Follow-up

Participants are monitored for changes in clinical biomarkers and health-related quality of life

4 weeks

Treatment Details

Interventions

• Precision Exercise Training

Trial Overview Researchers are testing if a personalized 12-week exercise program helps improve the ability of sepsis survivors to tolerate physical activity compared to usual care and lifestyle advice. Participants will do strength and aerobic exercises three times weekly and their progress will be measured against an attention control group.

Participant Groups

Group I: Exercise Intervention Experimental Treatment 1 Intervention

Patients will participate in a 12-week (36 sessions) precision exercise training intervention

Group II: Attention Control Active Control 1 Intervention

Patients will not receive exercise training but will be contacted 1x per week via phone to document self-reported physical activity and general wellbeing.

Who Is Running the Clinical Trial?

University of British Columbia

Lead Sponsor

Trials

1,506

Recruited

2,528,000+

St. Paul's Hospital, Canada

Collaborator

Trials

48

Recruited

13,200+

Providence Health & Services

Collaborator

Trials

131

Recruited

827,000+

Vancouver Coastal Health Research Institute

Collaborator

Trials

30

Recruited

5,600+

Simon Fraser University

Collaborator

Trials

59

Recruited

12,500+

Findings from Research

In a study of 516 sepsis patients admitted to the ICU, those with low skeletal muscle mass who received ICU-rehabilitation had significantly lower in-hospital and 6-month mortality rates compared to those who did not receive rehabilitation (26.0% vs. 39.8% and 38.6% vs. 51.5%, respectively).

ICU-rehabilitation was found to be independently associated with a 34% reduction in 1-year mortality for patients with low skeletal muscle mass, highlighting the importance of early rehabilitation in this vulnerable group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ICU rehabilitation is associated with reduced long-term mortality from sepsis in patients with low skeletal muscle mass: a case control study. Kim, T., Huh, S., Kim, SY., et al.[2022]

Aerobic exercise training significantly protects against sepsis-associated acute kidney injury (AKI) by enhancing the expression of R-spondin 3 (RSPO3), which helps maintain kidney function and integrity during sepsis.

The study found that exercise or RSPO3 administration reduced inflammation and endothelial damage in the kidneys, while knocking out RSPO3 worsened kidney injury, highlighting its crucial role in protecting against LPS-induced renal complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Increased R-spondin 3 contributes to aerobic exercise-induced protection against renal vascular endothelial hyperpermeability and acute kidney injury. Xu, QF., Zhang, H., Zhao, Y., et al.[2023]

Inadequate exercise significantly increases the risk of sepsis mortality, with a 2.24-fold higher risk for sepsis as an underlying cause and a 2.11-fold higher risk when sepsis is a contributing factor, based on a study of 155,484 participants over an average of 11.6 years.

The risk associated with inadequate exercise is particularly pronounced in individuals with diabetes, showing a 4.78-fold increase in sepsis mortality risk, highlighting the importance of regular physical activity for this vulnerable group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inadequate exercise as a risk factor for sepsis mortality. Williams, PT.[2021]

Early exercise rehabilitation combined with standard sepsis treatment showed potential benefits for functional recovery in patients with severe sepsis, particularly at hospital discharge.

In patients with higher severity scores (APACHE II ≥10), those who received the rehabilitation intervention demonstrated significantly greater improvements in physical function, as measured by the Modified Barthel Index and Functional Independence Measure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of Early Exercise Rehabilitation on Functional Recovery in Patients with Severe Sepsis. Ahn, JY., Song, JE., Ann, HW., et al.[2019]

Survivors of severe sepsis and septic shock showed significant physical inactivity during hospitalization, spending 90% of their time lying or sitting, which improved to 58% three months after discharge but still remained lower than healthy individuals.

Muscle strength and exercise capacity in these patients were only about 54% of predicted values at discharge, improving to 70% after three months, indicating a slow recovery process influenced negatively by factors like systemic corticosteroid use and longer hospital stays.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Physical activity, muscle strength, and exercise capacity 3 months after severe sepsis and septic shock. Borges, RC., Carvalho, CR., Colombo, AS., et al.[2022]

In a 12-week randomized controlled trial with 119 healthy young adults, aerobic exercise training did not lead to expected decreases in inflammatory markers TNF-α and IL-6, despite participants showing a 15% increase in aerobic capacity.

Interestingly, the study found that exercise initially increased levels of TNF-α and IL-6 in response to certain lipopolysaccharide levels, suggesting that aerobic training may provoke a temporary proinflammatory response rather than an anti-inflammatory effect.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aerobic Exercise Training and Inducible Inflammation: Results of a Randomized Controlled Trial in Healthy, Young Adults. Sloan, RP., Shapiro, PA., McKinley, PS., et al.[2023]

Individualizing exercise prescriptions is crucial for maximizing safety and effectiveness, as it helps reduce risks of injury and cardiac emergencies during exercise.

The effectiveness of exercise programs should be measured by improvements in aerobic power, muscular strength, and overall health, but patient responses can vary significantly, necessitating adjustments based on individual reactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exercise prescription: principles and current limitations. Shephard, RJ.[2021]

Dynamic strength training, especially at high intensities (≥70% of one-repetition maximum), significantly enhances muscle strength and power output in patients with cardiovascular disease, which can improve their overall prognosis.

High-intensity strength training is associated with fewer increases in blood pressure and cardiac output compared to low-intensity training, suggesting it may be a safer option for the cardiovascular system while still being effective.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dynamic strength training intensity in cardiovascular rehabilitation: is it time to reconsider clinical practice? A systematic review. Hansen, D., Abreu, A., Doherty, P., et al.[2020]

Resistance training (RT) is effective in increasing adiponectin levels and decreasing leptin and C-reactive protein levels, particularly in overweight and obese individuals, as shown in a systematic review of 17 studies.

Women may respond more positively to RT in terms of adiponectin, leptin, and C-reactive protein levels, and longer training durations (16 weeks or more) and higher intensities (over 80% of one repetition maximum) enhance these effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of resistance training on cytokines. de Salles, BF., Simão, R., Fleck, SJ., et al.[2018]

In a study involving 34 middle-aged obese men, both nonlinear resistance training (NRT) and aerobic interval training (AIT) significantly improved aerobic capacity compared to a sedentary control group, with AIT showing superior results in maximal oxygen uptake.

While both training types effectively reduced insulin resistance, AIT demonstrated better anti-inflammatory effects, as indicated by a significant increase in the IL-10:TNF-α ratio compared to the control group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of nonlinear resistance and aerobic interval training on cytokines and insulin resistance in sedentary men who are obese. Nikseresht, M., Agha-Alinejad, H., Azarbayjani, MA., et al.[2022]

Mice that engaged in low-intensity exercise during the acute phase of sepsis showed higher survival rates compared to sedentary mice, indicating that exercise may have a protective effect during sepsis.

Exercise increased fatty acid oxidation and levels of PGC-1α, a protein associated with energy metabolism, suggesting that physical activity helps mobilize energy sources and may improve outcomes in sepsis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low-intensity exercise in the acute phase of lipopolysaccharide-induced sepsis improves lipid metabolism and survival in mice by stimulating PGC-1α expression. Irahara, T., Sato, N., Inoue, K., et al.[2018]

Three weeks of moderate exercise training significantly improved survival rates in rats subjected to sepsis, indicating that fitness may be a modifiable risk factor for surgical outcomes.

The exercise training reduced inflammation and oxidative stress in the liver, restoring important antioxidant pathways, which suggests that exercise may enhance the body's immune response during systemic infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Moderate exercise-induced dynamics on key sepsis-associated signaling pathways in the liver. Osuru, HP., Ikeda, K., Atluri, N., et al.[2023]

Exercise training significantly lowers baseline arterial pressure, heart rate, and levels of harmful substances like methyl guanidine in rats, suggesting a protective effect against stress.

In response to endotoxin-induced sepsis, exercise-trained rats showed reduced inflammation and less severe damage to the heart, liver, and lungs compared to sedentary controls, indicating that exercise may help mitigate organ injury during septic conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exercise training attenuates septic responses in conscious rats. Chen, HI., Hsieh, SY., Yang, FL., et al.[2013]

References

1. China pubmed.ncbi.nlm.nih.gov

ICU rehabilitation is associated with reduced long-term mortality from sepsis in patients with low skeletal muscle mass: a case control study. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Increased R-spondin 3 contributes to aerobic exercise-induced protection against renal vascular endothelial hyperpermeability and acute kidney injury. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

Inadequate exercise as a risk factor for sepsis mortality. [2021]

4. Korea (South) pubmed.ncbi.nlm.nih.gov

Effects of Early Exercise Rehabilitation on Functional Recovery in Patients with Severe Sepsis. [2019]

5. United States pubmed.ncbi.nlm.nih.gov

Physical activity, muscle strength, and exercise capacity 3 months after severe sepsis and septic shock. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Aerobic Exercise Training and Inducible Inflammation: Results of a Randomized Controlled Trial in Healthy, Young Adults. [2023]

7. Canada pubmed.ncbi.nlm.nih.gov

Exercise prescription: principles and current limitations. [2021]

8. England pubmed.ncbi.nlm.nih.gov

Dynamic strength training intensity in cardiovascular rehabilitation: is it time to reconsider clinical practice? A systematic review. [2020]

9. Germany pubmed.ncbi.nlm.nih.gov

Effects of resistance training on cytokines. [2018]

10. United States pubmed.ncbi.nlm.nih.gov

Effects of nonlinear resistance and aerobic interval training on cytokines and insulin resistance in sedentary men who are obese. [2022]

11. United States pubmed.ncbi.nlm.nih.gov

Low-intensity exercise in the acute phase of lipopolysaccharide-induced sepsis improves lipid metabolism and survival in mice by stimulating PGC-1α expression. [2018]

12. England pubmed.ncbi.nlm.nih.gov

Moderate exercise-induced dynamics on key sepsis-associated signaling pathways in the liver. [2023]

13. United States pubmed.ncbi.nlm.nih.gov

Exercise training attenuates septic responses in conscious rats. [2013]