Chyme reinfusion using the Insides System to reduce parenteral nutrition dependence in Type 2 intestinal failure: multicentre randomised controlled trial (REINFUSE)

This multicentre randomised controlled trial demonstrates that device-assisted chyme reinfusion using the Insides System significantly reduces parenteral nutrition dependence and achieves complete cessation in a substantial proportion of patients with Type 2 intestinal failure due to double enterostomy or enterocutaneous fistula, while maintaining an acceptable safety profile.

The Gist

The Problem: A Broken Plumbing System

Imagine your digestive system as a complex plumbing network. In some patients, a major pipe (the intestine) has been cut or damaged, creating a "double leak" (a condition called Type 2 Intestinal Failure). Because the pipe is broken, food and liquid can't travel all the way through the body to be absorbed.

Instead of being absorbed, these nutrients and fluids leak out of the body through a stoma (an opening on the belly). To keep these patients alive, doctors must bypass the broken plumbing entirely and feed them directly into their veins through a tube. This is called Parenteral Nutrition (PN).

Think of PN as a "life-support IV drip" that acts as a temporary artificial gut. While it keeps patients alive, it has serious downsides:

• It requires a permanent tube in a major vein, which can get infected (like a dirty water pipe).
• It can clog the veins (like a blocked drain).
• It can damage the liver (like an engine running on bad fuel).
• It is expensive and keeps patients tied to a machine or hospital.

The Old Solution: The "Bucket and Hose" Method

Doctors have known for decades that if you could catch the leaking fluid from the top of the broken pipe and pour it back into the bottom of the pipe, the body might start working again. This is called Chyme Reinfusion Therapy (CRT).

However, doing this manually is like trying to catch rainwater in a bucket and pour it into a garden hose by hand. It is messy, difficult, and most people find the idea of handling their own digestive fluids very unpleasant. Because of this "gross factor" and the labor involved, this therapy was rarely used, even though it could theoretically fix the plumbing.

The New Solution: The "Insides" Robot

This study tested a new device called The Insides System. Think of this device as an automated, sanitary "recycling pump" for the gut.

Instead of a human having to scoop and pour, this system uses a small, battery-powered pump attached to the stoma bag. It sucks up the leaking fluid from the top, cleans it slightly, and pumps it back into the bottom of the intestine through a tube. It turns a messy, manual chore into a clean, automated process that patients can manage at home.

The Experiment: Testing the Pump

The researchers wanted to know: Does this automated pump actually help patients stop needing the IV drip (PN)?

They set up a large test (a Randomised Controlled Trial) involving 39 patients across the UK and the USA.

• The Control Group: These patients received standard care (just the IV drip and normal medical support).
• The Active Group: These patients received the standard care plus the Insides System pump to recycle their fluids.

They followed the patients for 60 days to see what happened.

The Results: The Pump Works

The study found that the group using the "Insides" pump had much better outcomes than the group that didn't:

1. Stopping the IV Drip: By day 60, 43% of the patients using the pump were able to stop the IV nutrition completely. In the control group, zero patients were able to stop.
2. Reducing the Leak: The pump helped the body absorb more water. The amount of fluid leaking out of the body dropped by about 70% in the pump group.
3. Safety: The device was safe. Most side effects were minor (like a little skin irritation where the tube went in). One patient died, but the doctors confirmed it was due to a heart/blood vessel issue unrelated to the pump.
4. Happiness: Patients who used the device were very happy with it. They found it easy to use and felt it gave them their lives back.

The Bottom Line

This study is the first time this specific "recycling pump" has been tested in a rigorous, scientific way against a control group.

The paper claims that for patients with this specific type of broken gut (double leaks), using this device allows a significant portion of them to stop relying on the dangerous and expensive IV nutrition and start absorbing food and water naturally again. It turns a messy, difficult manual task into a clean, automated solution that helps the body heal itself.

In short: The "Insides" system acts like a smart recycling plant for your gut, catching the waste and feeding it back in, which helps the body repair the broken pipe and stop needing the IV life-support.

Technical Summary

1. Problem Statement

Clinical Context: Type 2 Intestinal Failure (T2IF) caused by double enterostomy (DES) or enterocutaneous fistula (ECF) results in the inability to absorb sufficient fluids and nutrients, necessitating long-term Parenteral Nutrition (PN).
Current Challenges:

• High Morbidity/Mortality: Long-term PN carries significant risks, including central venous catheter (CVC) sepsis (0.22–11.5 events per 1,000 catheter days), venous thrombosis, intestinal failure-associated liver disease (IFALD), and a 10-year mortality rate of up to 39%.
• Economic Burden: Home PN costs up to £73,000/year, with inpatient costs reaching £1,000/day.
• Therapeutic Gap: Chyme Reinfusion Therapy (CRT)—refeeding proximal bowel contents into the distal bowel to restore function—has been shown in non-randomized studies to reduce PN dependence. However, manual reinfusion is labor-intensive and unpleasant, leading to low adoption. No Randomized Controlled Trials (RCTs) had previously validated device-assisted CRT.

2. Methodology

Study Design:

• Type: Multicentre, open-label, randomised controlled trial (RCT).
• Setting: 12 centres across the UK and USA.
• Participants: 39 adults (26 Active, 13 Control) with T2IF due to DES/ECF, dependent on PN for ≥2 weeks, with intubatable distal limbs.
• Exclusion Criteria: Insufficient distal limb length, proximal obstruction, active sepsis, severe hepatorenal failure, or specific motility disorders.
• Randomisation: 2:1 allocation (Active:Control) using block randomisation, stratified by DES vs. ECF.

Interventions:

• Active Group: Standard care + The Insides® System. This device consists of a distal catheter (22Fr/28Fr), an impeller pump connected to the stoma appliance, and an external battery-driven driver. It automates the collection and reinfusion of chyme.
• Control Group: Standard care (PN) per ASPEN/ESPEN guidelines.
• Duration: 60-day follow-up period post-randomisation.

Endpoints:

• Primary: Proportion of participants achieving a ≥50% reduction in PN caloric intake at Day 30 (Intention-to-Treat analysis).
• Secondary: Complete cessation of PN at 30/60 days, reduction in intestinal losses, Quality of Life (QoL), Nutrition Risk Index (NRI), and safety/adverse events.
• Statistical Adjustment: Due to a planned interim analysis, the significance threshold for the primary endpoint was adjusted to $p < 0.025$.

3. Key Contributions

• First RCT Evidence: This is the first randomised controlled trial to evaluate device-assisted CRT, moving beyond historical cohort studies to provide high-level evidence.
• Technological Innovation: Demonstrates the feasibility and efficacy of The Insides System, which solves the historical barriers of manual chyme handling (labor intensity and patient aversion) through automation.
• Clinical Paradigm Shift: Establishes that early intervention with device-assisted CRT can significantly alter the trajectory of T2IF management, potentially avoiding long-term PN dependence and associated complications.

4. Results

Primary Endpoint (Day 30):

• Active Group: 8/26 (31%) achieved ≥50% reduction in PN calories.
• Control Group: 0/13 (0%).
• Statistical Significance: $p = 0.035$. While statistically significant in a standard test, it did not meet the pre-specified adjusted threshold of $p < 0.025$ due to the interim analysis correction.

Secondary Endpoints (Day 60):

• PN Cessation: 10/26 (43%) of the active group completely ceased PN compared to 0% of controls ($p = 0.008$).
• PN Reduction: 38% of the active group achieved ≥50% reduction vs. 0% controls ($p = 0.016$).
• Intestinal Losses: The active group showed a median reduction in losses of -1,344 mL/day at Day 30 and -1,450 mL/day at Day 60, compared to minimal changes in controls ($p = 0.005$ and $p = 0.026$, respectively).
• Nutritional Status: The active group's median Nutrition Risk Index (NRI) improved from 97.3 to 107.3, while the control group declined slightly. The proportion of active patients with "no malnutrition risk" increased from 43.5% to 66.7%.
• Quality of Life: Satisfaction with the device was very high (median 46/50). QoL and depression scores were comparable between groups.

Safety:

• Adverse Events: Device-related adverse events were predominantly mild (6 mild, 4 moderate, 1 severe).
• Serious Adverse Events (SAEs): 14 SAEs in the active group vs. 2 in controls. However, only 2 SAEs were device-related (peristomal skin irritation requiring hospitalization).
• Mortality: One death occurred in the active group (Day 5) due to vascular occlusion; adjudicated as unrelated to the device.

5. Significance and Impact

• Clinical Efficacy: The study proves that device-assisted CRT can enable 43% of eligible T2IF patients to stop PN entirely within 60 days, a rate significantly higher than historical controls and comparable drug therapies (e.g., teduglutide in short bowel syndrome).
• Safety Profile: The therapy is safe, with a low rate of device-related complications, primarily manageable skin irritation.
• Economic & Systemic Impact: By reducing PN dependence, the therapy mitigates risks of sepsis, liver disease, and thrombosis. It offers substantial cost savings by reducing home PN requirements and hospital stays.
• Rehabilitation: CRT restores distal bowel function and trophic stimulation, potentially optimizing patients for future reconstructive surgery (stoma closure).
• Future Standard of Care: The authors argue that early initiation of device-assisted CRT should become standard care for suitable DES/ECF patients to facilitate rehabilitation, improve psychological wellbeing, and reduce healthcare costs.

Limitations Noted:

• The primary endpoint missed the adjusted statistical significance threshold ($p=0.035$ vs. $p<0.025$), largely attributed to slower PN weaning protocols in the UK/US centers compared to historical French cohorts.
• Low recruitment from US centers (2 participants) due to lack of prior CRT experience.
• Open-label design (unblinded), though objective endpoints (PN volume) were used.