Rodents and pigs have the ability to use their intestines for respiration


Rodents and pigs share with certain aquatic organisms the ability to use their intestines for respiration, finds a study publishing May 14th in the journal Med. The researchers demonstrated that the delivery of oxygen gas or oxygenated liquid through the rectum provided vital rescue to two mammalian models of respiratory failure.

“Artificial respiratory support plays a vital role in the clinical management of respiratory failure due to severe illnesses such as pneumonia or acute respiratory distress syndrome,” says senior study author Takanori Takebe of the Tokyo Medical and Dental University and the Cincinnati Children’s Hospital Medical Center.

“Although the side effects and safety need to be thoroughly evaluated in humans, our approach may offer a new paradigm to support critically ill patients with respiratory failure.”

Several aquatic organisms have evolved unique intestinal breathing mechanisms to survive under low-oxygen conditions using organs other than lungs or gills. For example, sea cucumbers, freshwater fish called loaches, and certain freshwater catfish use their intestines for respiration. But it has been heavily debated whether mammals have similar capabilities.

In the new study, Takebe and his collaborators provide evidence for intestinal breathing in rats, mice, and pigs. First, they designed an intestinal gas ventilation system to administer pure oxygen through the rectum of mice.

They showed that without the system, no mice survived 11 minutes of extremely low-oxygen conditions. With intestinal gas ventilation, more oxygen reached the heart, and 75% of mice survived 50 minutes of normally lethal low-oxygen conditions.

Because the intestinal gas ventilation system requires abrasion of the intestinal muscosa, it is unlikely to be clinically feasible, especially in severely ill patients – so the researchers also developed a liquid-based alternative using oxygenated perfluorochemicals. These chemicals have already been shown clinically to be biocompatible and safe in humans.

The intestinal liquid ventilation system provided therapeutic benefits to rodents and pigs exposed to non-lethal low-oxygen conditions. Mice receiving intestinal ventilation could walk farther in a 10% oxygen chamber, and more oxygen reached their heart, compared to mice that did not receive intestinal ventilation.

Similar results were evident in pigs. Intestinal liquid ventilation reversed skin pallor and coldness and increased their levels of oxygen, without producing obvious side effects. Taken together, the results show that this strategy is effective in providing oxygen that reaches circulation and alleviates respiratory failure symptoms in two mammalian model systems.

With support from the Japan Agency for Medical Research and Development to combat the coronavirus disease 2019 (COVID-19) pandemic, the researchers plan to expand their preclinical studies and pursue regulatory steps to accelerate the path to clinical translation.

“The recent SARS-CoV-2 pandemic is overwhelming the clinical need for ventilators and artificial lungs, resulting in a critical shortage of available devices, and endangering patients’ lives worldwide,” Takebe says.

“The level of arterial oxygenation provided by our ventilation system, if scaled for human application, is likely sufficient to treat patients with severe respiratory failure, potentially providing life-saving oxygenation.”

Until recently, most studies reported the mortality from acute lung injury and acute respiratory distress syn- drome (ARDS) to range from 40% to 60%.1 Although a number of improved approaches to conventional me- chanical ventilation have been proposed and some ad- vantages and benefits have been reported,2–4 the current techniques of ventilatory management are often associ- ated with relatively high inspiratory airway pressures (barotrauma), overdistension of the normal lung region (volutrauma), and toxic levels of inspired oxygen. Extracorporeal membrane oxygenation (ECMO) is a last resort for acute respiratory failure.

The indications for ECMO include acute reversible respiratory or cardiac failure, and patients who are unresponsive to optimal ventilator and pharmacologic management; the predicted mortality rate is 80%.4

Although occasionally successful as a bridge to transplant, ECMO requires multiple transfusions and this treatment mo- dality is complex, labor-intensive, time-limited, costly, nonambulatory, and infection-prone.4 As a last resort, lung transplantation is obviously limited by the scarcity of donor lungs.

Even though a great deal of experimental and clinical efforts have been made,5–8 the number of procedures has not increased dramatically;9 as a result, only a few candidate patients are thus able to undergo transplantation.

Unlike dialysis, which functions as a bridge to renal transplantation, or a ventricular assist device, which serves as a bridge to cardiac transplantation, no suitable bridge to lung transplantation exists.4 For these reasons,
a more simple, durable, and effective modality of respiratory assist, which would ideally not be dependent on the patient’s lungs, is thus desirable.

Perfluorocarbon has an excellent oxygen- and carbon dioxide-carrying capacity (50 ml O2/dl and 160–210 ml CO2/dl, respectively),10 and for this reason  it  has  been studied and used in a novel mechanical ventilation setting (i.e., liquid ventilation). Although clinical stud- ies found liquid ventilation to be safe in patients with acute lung injury and early ARDS, neither an improve- ment in survival nor a decrease in ventilator requirement has been demonstrated.11

Aside from extensive studies on liquid ventilation, there have been few animal studies of transperitoneal oxygenation using perfluorocarbon12,13 in which systemic oxygenation was elicited. In addition, the level of oxygenation by perito- neal perfusion was so low that it appears to be insuffi- cient for respiratory assist in a clinical setting.

It was suspected that the low level of oxygenation was mainly due to the paucity of the blood flow on the peritoneal surface. This phenomenon, however, gave us the idea to use the intestine as an oxygenator, instead. In addition, several studies in which intraluminal oxygenated perfluorocarbon demonstrated a protective effect against intestinal ischemia in animal models further reinforced this idea.14,15

The small intestine receives 12% of the cardiac output,16 and the membrane has abundant capillaries. Although the amount of blood perfusing the small intestine is small, if sufficient systemic oxygenation occurs through the membrane, a form of respiratory support that does not depend on the lungs may thus be possible. Therefore, we examined the feasibility of transintestinal oxygenation using the intraluminal perfusion of perfluorocarbon.

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More information: Ryo Okabe et al, Mammalian enteral ventilation ameliorates respiratory failure, Med (2021). DOI: 10.1016/j.medj.2021.04.004Perfluorocarbon has an excellent oxygen- and carbon dioxide-carrying capacity (50 ml O2/dl and 160–210 ml CO2/dl, respectively),10 and for this reason  it  has  been studied and used in a novel mechanical ventilation


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