In our rat model of hypoxemia, the infusion of pure O2 gas through a central vein was unfeasible as it induced early death due to pulmonary embolism. The infusion of oxygenated Hartmann’ solution over 3 h was safe; however, it proved ineffective in increasing blood or tissue oxygenation. Similarly, the administration of gaseous O2 into the small bowel did not produce any improvement in oxygenation although it was not associated with any unfavorable effects.
Numerous attempts have been made in the past to oxygenate the blood by routes other than the lung. Nysten was probably the first to inject gaseous O2 into the veins of a living animal in 1811 [10]. The first administration to a human being dates back to 1902, when Mariani reported an improved pulse and respiration following the infusion of 120 ml O2 over 15 min through the dorsalis pedis vein in a patient with tuberculosis, but who died the next day [11]. Several other investigators reported encouraging results in both animals and humans [4, 12–14]; however, these data were not confirmed by others. It became clear that the intravenous administration of pure O2 gas could lead to pulmonary embolism and worsened blood oxygenation [15, 16]. It was also suggested that only a small amount of the gas injected could be absorbed as only a minimal surface of gas was in direct contact with the blood due to the coalescence of gas bubbles [16]. Our study in hypoxemic rats supports the lack of safety of intravenous gas infusion. We used an O2 infusion rate of 2 ml/kg/h, which would correspond to an infusion rate of 140 ml/h for a human weighing 70 kg. There are case reports showing that the intravenous bolus injection of 100 ml of air can cause cardiac arrest due to fatal pulmonary embolism [17]. Other authors suggest the lethal dose for humans to be 3–5 ml/kg and that a rapid injection of 300–500 ml at a rate of 100 ml/s is fatal [18]. A larger amount of O2 may be potentially administered in humans or large animals using peripheral venous accesses and lower rates of infusion without hemodynamic or respiratory sequelae. However, scientific evidences for this are lacking, and the questions as to whether a sufficient volume of gas could be administered safely and absorbed to effectively improve tissue oxygenation remain unanswered.
Despite being safe, the intravenous infusion of oxygenated Hartmann’s solution was not able to induce any increase in blood or tissue PO2. In an experimental study in normoxemic rabbits, Kim et al. reported an increase in arterial PO2 during the administration of oxygenated Ringer’s lactate through a central vein [19]. However, spontaneous variation cannot be excluded as no control group was used in this study. The PO2 of solution at end-experiment in our study was even higher (87.5 ± 1.7 kPa) than that reported by Kim et al. (76.7 kPa); however, it must still be acknowledged that the amount of O2 dissolved remains small. In our experiments, at 60 min hypoxemia, the average O2 delivery (DO2) was 14.4 ± 2.6 ml/min (as calculated from the cardiac output, Hb levels, SaO2, and PaO2) and the O2 consumption (VO2) was 5.9 ± 1.2 ml/min (as calculated from the cardiac output and the difference between the arterial and venous O2 content). According to the Henry’s law and the ideal gas law, at PO2 = 100 kPa and temperature = 20 °C, we can estimate that the amount of O2 dissolved in the oxygenated Hartmann’ solution was about 0.03127 ml O2/ml. At a fluid infusion rate of 10 ml/kg/h, a rat weighing 300 g received around 0.05 ml/min (3 ml/h) of Hartmann’ solution, containing 0.0016 ml O2/min. This represents about the 0.01 % of the total DO2 and the 0.027 % of the total VO2, thus making an insignificant contribution to systemic oxygenation.
In a guinea pig experiment, Kellogg noted that the dark blood in the portal veins assumed a bright red color soon after the injection of O2 into the rectum, suggesting a rapid absorption through the intestinal wall [5]. In a case series, Maruzok et al. reported a significant increase in the PaO2/FiO2 ratio in patients with acute respiratory distress syndrome following the intestinal insufflation of pure O2 gas through a naso-intestinal tube [20]. As the improvement in systemic oxygenation lasted for more than 32 h, direct intestinal absorption of O2 seemed unlikely [20]. Again, the lack of a control group prevents definitive conclusions from being drawn. In our study in hypoxemic rats, the administration of pure O2 gas into the small bowel was unable to produce any increase in systemic oxygenation, either rapidly (during infusion) or in the 2 h following infusion discontinuation. The liver should have been the first organ to benefit from an intestinal absorption of O2 into the portal veins for anatomical reasons. The observed trend towards a reduction in arterial lactate levels during the administration of bowel O2 might reflect an improved hepatic metabolism. However, no improvement was seen in liver tPO2 during or after the insufflation of O2 into the bowel. By administering a 5-ml bolus of pure O2 followed by a continuous infusion of 50 ml/kg/h, we infused a total of 27.5 ml of pure O2 for a rat weighing 300 g (5 ml + 15 ml/h over 90 min). Even if all this O2 had been absorbed in the circulating blood over time, this would have contributed to systemic oxygenation only by about 2 % of the systemic DO2 (total DO2 over 90 min under FiO2 10 % = 1296 ml) and 4.2 % of systemic VO2 (total VO2 over 90 min under FiO2 10 % = 531 ml). Our results do not show any evidence supporting the ability of O2 to be absorbed in a detectable amount through the intestinal mucosa into the blood.
Other alternatives to pulmonary oxygenation have been explored over the past years. Perfluorocarbon-based O2 carriers have been tested using several routes of administration, including intravenous [21], transintestinal [22], and transpleural [23], as well as for liquid ventilation [24]. Nevertheless, none of these agents has been approved for clinical use due to storage, production, and clinical evaluation complications [25]. Kheir et al. manufactured lipid-based O2-carrying microbubbles for intravenous infusion that could rescue hypoxemia in asphyxiated rabbits, decreasing the incidence of cardiac arrest and organ injury without inducing any signs of pulmonary embolism [26]. The administration of phospholipid-coated O2 microbubbles into the peritoneal cavity was effective in increasing systemic oxygenation in animal models of pneumothorax [27] and asphyxia [28]. The research for simple, non-invasive, and cheap alternatives to pulmonary oxygenation is still ongoing, and further studies are encouraged.
Some limitations of our study need to be acknowledged. Firstly, retrospective theoretical calculations of the amount of O2 administered in the different models clearly show that the experimental approach applied was unsuitable to produce any positive results. However, we designed our experiments based on previously published reports [4, 5, 10–16, 19, 20] that represented our proof of concept. Secondly, we constructed an artificial short-term model of hypoxemia by administering a hypoxic gas mixture. Other experimental models of acute respiratory distress syndrome (e.g., by repeated pulmonary lavage [29]) could more closely reproduce the clinical scenario. However, our method allowed a better control of the amount of O2 absorbed in the lungs, thus limiting variability in oxygenation parameters. Other potential routes for O2 administration were not evaluated, such as the peritoneal route. Mechanical ventilation of the peritoneal cavity was able to improve oxygenation in an experimental model of acute respiratory syndrome in rabbits, inducing both an increase in arterial PO2 and a decrease in arterial PCO2 [30].
