Preclinical mammalian models, including pigs and mice, can breathe in the intestines, which can provide an additional route of oxygen delivery to patients in need of airway support.
Asuka Kodaka, YCU
V.Ventilators – machines that push air into the lungs – can save lives for patients who cannot breathe on their own due to injury or illness. However, they can also cause lung damage due to the amount of pressure they exert. In addition, the number of ventilators is limited, which resulted in critical shortages during the COVID-19 pandemic.
In a study published today (May 14) in MedResearchers present an alternative way of supplying oxygen: through the anus. They introduced oxygen in gaseous or liquid form into the intestines of mice and pigs that had experienced asphyxiation or deoxygenated conditions and showed that the animals survived much longer than those without treatment.
“I’ve never read or thought about ventilation with the enteral system,” said Divya Patel, a pulmonologist and intensive care doctor at the University of Florida College of Medicine who was absent from the work. “Mechanical fans are a bridge. They give us time for the body to heal. [but] The problem with them is that they also injure the lungs themselves, ”she explains. These authors are “really open-minded and think outside the box”.
I have never read or thought about ventilation with the enteral system.
– Divya Patel, University of Florida Medical School
Takanori Takebe, who is affiliated with Cincinnati Children’s Hospital, Tokyo Medical and Dental University, and Yokohama City University, typically focuses on manipulating stem cells to grow functioning human organs in a Petri dish. Three years ago, his father, who had chronic lung disease, developed acute respiratory distress syndrome (ARDS) – a lung complication that can be fatal and common in patients with severe COVID-19 – and required ventilation. His father survived, but the experience impressed Takebe with how limited treatments for respiratory failure are.
“The standard of care is really detrimental to native lung function,” he says. His father now has impaired lung function, which is not uncommon in ventilated patients, especially over long periods of time. “I realized that we needed different types of breathing assistance without touching the native lungs,” he adds.
Takebe and his team read and learned that many organisms – including fish like loaches and arthropods – use organs like the skin and intestines to get oxygen. To see if mammals have such abilities, they started with mice. Mice given hypoxic air through their trachea survived an average of 18 minutes when the researchers introduced oxygen gas into their intestines through their anus, but only about 11 minutes without it. When the researchers rubbed the intestinal lining with a brush and then introduced oxygen gas, most of the animals survived at least 50 minutes.
“If you use lethal hypoxic conditions in the mouse and provide enteral oxygen, survival doubled over time,” he explains. “That gives us a lot more time to manage the condition to actually build a bridge until treatment is available.”
Next, the researchers tried a more practical method than grinding the lining of the intestine and pumping in gas: introducing an oxygenated liquid known as a perfluorocarbon through the anus. In previous clinical studies, perfluorocarbons, which carry dissolved oxygen, have been administered directly into human eyes and blood vessels, as well as into the airways of premature babies to reduce lung injury. The researchers infused either the rectum of mice in a deoxygenated chamber with either oxygenated perfluorocarbon or saline. The animals that received the oxygenated fluid showed improvements in oxygen pressure in their blood and were more active than the mice that received saline after their perfluorocarbon infusion.
The team then tested the oxygenated fluids strategy on anesthetized pigs, which share more physiology with humans than mice. They used a ventilator only five or six times per minute to induce non-lethal respiratory failure and then rescued the pigs from hypoxia with an enema-type administration of oxygenated perfluorocarbon and observed no apparent side effects. To further test safety, they performed perfluorocarbon infusions into the intestines of rats. The rats were not dehydrated, had no diarrhea, and the levels of organ toxicity markers were equal to or lower than those observed with the saline solution.
The vascular network is marked purple in this picture of a dissected mouse intestine. Takebe and colleagues hypothesize that the mammalian gut provides access to this network of blood vessels for possible gas exchange.
Yosuke Yoneyama and Akiko Kinebuchi, TMDU
These findings are “an example of evolution tinkering with a system that probably evolved with a different purpose – to digest food and move nutrients around the body – and then co-opt that system to do something else that is really useful to the organism, ”says Art Woods, a biologist at the University of Montana. He wasn’t involved in the new study, but in a 2017 paper that inspired them, he and colleagues showed that spider crabs use their intestines to carry oxygen. “It’s pretty smart to do this in some way as a medical technique,” he adds.
Based on the US Food and Drug Administration’s prior approval of perfluorocarbons for other indications, “We are very optimistic about safety [and] Tolerance when used in humans, ”says Takebe. He and his colleagues are founding a startup company to carry out further preclinical safety analyzes and evaluate further animal disease models. He hopes to start clinical trials in the next year, but warns that it is not yet clear whether improving oxygenation through this method would be helpful in coronavirus patients. “COVID-19 is not just about ARDS or a problem with oxygen supply to the lungs, but there are a number of different pathologies,” he explains.
“Understanding the mechanism would help encourage people to adopt it and explore further,” says Patel. Other steps include studying the effectiveness of the strategy in an ARDS or pneumonia model, as well as examining the safety for this perfluorocarbons use in humans, she adds. If the technique proves effective and safe, it could “possibly be a way to avoid the mechanical ventilator or set it to very low settings so you don’t cause this ventilator-induced lung injury.”
R. Okabe et al., “Enteral Ventilation in Mammals Improves Respiratory Failure”. Med, doi: 10.1016 / j.medj.2021.04.004, 2021.