Exogenous surfactant therapy for neonatal respiratory distress syndrome (Fujiwara)

Hyaline membrane disease, the pathological term for what clinicians now call neonatal respiratory distress syndrome, was the leading cause of death in premature infants through the 1960s and 1970s. The underlying problem had been identified by Mary Ellen Avery and Jere Mead in 1959: lungs of affected infants lacked sufficient surfactant, the complex mixture of phospholipids and proteins that reduces alveolar surface tension and prevents alveolar collapse at end-expiration. Without it, each breath required enormous effort to reinflate collapsed alveoli, and infants fatigued quickly. Treatment was supportive, primarily supplemental oxygen and, later, mechanical ventilation, with no way to address the underlying deficiency.

Tetsuro Fujiwara at Iwate Medical University in Morioka, Japan, spent years working out whether exogenous surfactant could be delivered safely into the trachea of living infants. The preparation, known as Surfactant-TA, was a modified extract of minced cow lung containing surfactant proteins B and C, supplemented with synthetic lipids. Animal experiments preceded the human work, providing both the biological rationale and safety data necessary to proceed.

In 1980, Fujiwara's team published results in the Lancet from ten very preterm infants with hyaline membrane disease who received intratracheal surfactant. Oxygenation improved, inspired oxygen and peak ventilator pressure could be reduced, many of the X-ray abnormalities resolved, and acidosis and low blood pressure were reversed. Eight of the ten infants survived, including five of the six who weighed under 1500 grams at birth; the two deaths were from unrelated causes. In nine infants a patent ductus arteriosus appeared after recovery and required further ventilation.

The Lancet publication attracted immediate interest from neonatologists in Europe and North America, who began designing controlled trials to confirm the findings and establish optimal dosing and timing. Trials through the mid-1980s compared natural surfactant extracts against synthetic preparations, prophylactic versus rescue administration, and single versus multiple doses. The FDA approved the first commercial preparation, the protein-free synthetic surfactant Exosurf Neonatal, on August 2, 1990, and the calf-lung surfactant beractant (Survanta) on July 1, 1991.

Surfactant replacement therapy, used alongside antenatal corticosteroids introduced by Graham Liggins and Ross Howie in the 1970s, and continuous positive airway pressure for spontaneously breathing infants, substantially reduced RDS mortality through the 1990s. For infants with RDS weighing under 1500 grams, survival rose from about 5 percent in the 1960s to over 90 percent today. Later comparisons found that natural surfactants worked better and caused fewer complications than the first synthetic ones.