Transrectal Oxygen Delivery: Emerging Evidence for an Auxiliary Gas Exchange Pathway

Acute hypoxemic respiratory failure continues to stretch the limits of modern critical care, where every second of lost oxygenation can determine outcome. Standard interventions, whether non-invasive ventilation, mechanical ventilation, or extracorporeal oxygenation, remain essential but come with substantial invasiveness, technical complexity, and dependence on specialized resources. Into this highly constrained clinical landscape enters an unexpected proposal from Takanori Takebe, MD, PhD: that the human rectal mucosa, long known for its absorptive efficiency, might be repurposed as a transient conduit for oxygen delivery.

This idea, while unconventional, does not arise from speculation. It is anchored in comparative physiology, where intestinal gas exchange supports survival in several species, and in the remarkable gas-carrying capacity of perfluorocarbon liquids. Takebe’s group has begun translating these biological principles into a controlled medical application, producing early animal data and initial human tolerability findings that together outline a scientifically coherent and clinically provocative, adjunct to traditional oxygenation strategies.

Scientific Rationale

The intestinal mucosa is densely vascularized, with a surface architecture permissive to rapid molecular diffusion. Perfluorodecalin, a clinically used perfluorocarbon, possesses high solubility for both oxygen and carbon dioxide. When oxygen-saturated and delivered intrarectally, the liquid theoretically establishes a gradient that enables:

• Passive diffusion of O₂ from the lumen into the capillary network.
• Uptake of CO₂ into the liquid, mimicking aspects of alveolar gas exchange.
• This mechanism parallels alternative respiratory strategies observed in several aquatic species, such as loaches, which supplement gill function with intestinal air absorption during hypoxic stress.

Preclinical Evidence

Takebe’s group and collaborators conducted proof-of-concept studies in rodent and porcine models. Oxygen-rich perfluorodecalin enemas produced measurable and time-limited improvements in systemic oxygenation. In pigs, single 400-mL doses elevated arterial oxygen saturation for approximately 15–20 minutes, with larger volumes sustaining effects for up to 30 minutes. These findings demonstrated:

• Feasibility of transintestinal oxygen transfer.
• Adequate hemodynamic stability during administration.
• Visible conversion of deoxygenated to oxygen-rich blood, indicating real-time gas exchange.

These preclinical results established both biological plausibility and dose–response characteristics useful for designing human studies.

A phase I safety and tolerability trial was conducted in 27 healthy male adults in Japan. Participants received non-oxygenated perfluorodecalin via the rectum in escalating volumes (25 mL to 1.5 L), retained for approximately one hour.

First-in-Human Safety Assessment

Key safety outcomes

• Volumes up to 1.0 L were generally well tolerated, with reports of mild abdominal distension and transient discomfort.
• 1.5 L doses resulted in abdominal pain in four of six participants, prompting early termination of infusion.
• No serious adverse events or clinically significant mucosal injury were documented.
• Pharmacokinetic and systemic absorption data showed no toxic accumulation of the compound.

This study confirmed that the procedure is feasible and safe enough to justify subsequent trials using oxygen-enriched formulations aimed at assessing functional efficacy.

Clinical Significance and Potential Uses

If future trials confirm clinically meaningful oxygen transfer in humans, transrectal oxygen delivery could serve as a temporary adjunct, not a replacement for pulmonary ventilation.

Potential applications include:

1. Emergency Airway Management

During endotracheal intubation, even brief interruptions in oxygen supply can trigger life-threatening desaturation. A short boost in oxygenation could improve patient safety during complex or prolonged procedures.

2. Transport Between Facilities

Transporting critically ill patients often involves periods where ventilatory support is less stable. A transient, low-risk oxygenation method could reduce hypoxic episodes during ambulance or interfacility transfer.

3. Resource-Limited Settings

In mass-casualty events, remote environments, or hospitals lacking ventilators, a temporary oxygenation method may sustain patients until standard respiratory support becomes available.

4. Adjunctive Support in Severe Pulmonary Disease

In specialized cases, such as advanced ARDS or intraprocedural hypoxia, enteral oxygenation could be layered onto existing therapies, similar to how ECMO or high-flow nasal cannula complement conventional ventilation.

Skepticism and Scientific Debate

The concept has divided the critical care community.

Concerns Raised by Experts

• Clinicians like Dr. John Laffey (University of Galway) argue that:
• The lung’s gas-exchange capacity far exceeds that of any other organ.
• Effective long-term oxygenation would require large, repeated PFD doses.
• Practical implementation could be difficult in unstable patients.
• Back-of-the-envelope calculations suggest that matching even minimal ventilatory oxygen flow may be unrealistic.

Supportive Perspectives

• Others, including Dr. Kevin Gibbs (Wake Forest University), view it as:
• A potentially valuable short-term bridge, not a primary oxygenation strategy.
• A novel intervention that might benefit rare but critical scenarios such as pre-intubation stabilization.

This balance of skepticism and cautious optimism reflects the early developmental stage of the technology.

Challenges Ahead

• For clinical translation, investigators must address:
• Scaling oxygen delivery to meaningful physiologic levels.
• Ensuring mucosal integrity under repeated dosing.
• Managing patient comfort and tolerability.
• Developing standardized dosing protocols.
• Long-term effects on rectal microbiota and mucosal health.
• Device engineering for oxygenation, administration, and monitoring.

Only robust Phase I–III clinical trials can determine whether the technique offers real-world therapeutic value.

Future Directions

Several avenues are currently under exploration:

Higher-efficiency oxygen carriers, including modified perfluorocarbons.

Microbubble-based formulations, which may greatly increase luminal gas-surface area.

Non-invasive mucosal priming, using mild surfactants instead of abrasion.

Hybrid systems that combine enteral and pulmonary oxygenation.

While widespread clinical adoption remains years away, the research reopens fundamental discussions about the flexibility of human physiology.

Conclusion

Transrectal oxygen delivery represents a scientifically grounded, technically innovative approach to emergency oxygenation. Early animal and human data show feasibility and safety of the delivery vehicle, while significant challenges remain regarding efficacy in humans. Whether this approach becomes a niche clinical tool or remains an experimental curiosity will depend on upcoming clinical trials.

Regardless of its eventual clinical role, the work highlights the value of exploring unconventional physiologic pathways and underscores the urgency of developing new adjuncts for respiratory support in critical care medicine.

References

• Okabe R. et al., Mammalian enteral ventilation ameliorates respiratory failure, Med (Cell Press), 2021.
• Fujii T. et al., Enteral liquid ventilation oxygenates a hypoxic pig model, iScience, 2023.
• Fujii T. et al., Safety and tolerability of intrarectal perfluorodecalin for enteral ventilation (first-in-human safety study), Med, 2025.