Following up on Kylstra's work, Leland Clark showed that a class of chemicals called perfluorochemicals, developed during the Manhattan Project, can be used as a excellent medium for liquid breathing.  Clark demonstrated, under normobaric conditions, that mice and rats could survive while submerged in a beaker of oxygenated perfluorochemical fluid for a prolonged period of time and could be recovered to gas breathing without deleterious effects.

In 1970, the concept of demand-regulated liquid ventilation was introduced by Gordon Moskowitz and later developed by Thomas Shaffer. This scheme of liquid breathing allowed for the control of movement of oxygenated PFC to and from the lungs while spontaneously breathing. The advantages of liquid ventilation includes uniform distribution of PFC fluid in the lungs, reduction of the high surface tension of the gas-lung interface, alveolar recruitment at low alveolar pressures and increased pulmonary compliance in an injured or surfactant deficient lung.

The advantages of PFC liquids as a breathing medium were demonstrated by Shaffer and Maria Delivoria-Papadopulos in 1976 when they showed gas exchange and acid-base balance in premature lambs improved during liquid ventilation. Further studies by Shaffer also reported improve lung compliance during liquid ventilation.

In 1978, Shaffer demonstrated, the efficacy of PFC on lung mechanics in premature lambs, when used in combination with a conventional gas ventilator.

In 1992, Marla Wolfson demonstrated in a head-to-head study comparing liquid ventilation to gas ventilation in premature lambs born during the canalicular stage of lung development that there was better gas exchange, respiratory compliance and cardiovascular stability in the liquid ventilation group as compared to gas ventilation. Furthermore, the lung of the  liquid ventilation group appeared clear with thin walls and the gas exchange spaces were uniformly expanded, free of hyaline membranes and luminal debris. In contrast, the gas ventilated lungs demonstrated non-homogenous lung expansion with thick-walled gas exchange spaces containing protinaceous exudate, hemorrhage and hyaline membranes.

In 1998 Wolfson and Shaffer tested the hypotheses that liquid ventilation after surfactant treatment would improve pulmonary function and histology. They found that  liquid ventilation of the surfactant-treated lung improves gas exchange and lung mechanics. The protective benefits of perflubron in the lung may depend on dose and ventilator strategy to optimize PFC distribution and minimize exposure of the alveolar-capillary membrane to a gas-liquid interface.

Following up on extensive experimental work, in 1989  Jay Greenspan, Thomas Shaffer, Marla Wolfson, and David Rubenstein conducted the first human trials with three moribund premature infants using two 3 to 5 minute cycles of liquid ventilation by means of gravity-assist and returning to gas ventilation. These studies demonstrated that there was an improvement in lung mechanics as well as gas exchange.

Neonatal Liquid Ventilation