How does exogenous surfactant really work?

Abstract

The finding of a lag of up to 24 h between the response to exogenous surfactant in infants with respiratory disease syndrome as assessed by blood gases and improvements in respiratory system compliance has generated considerable interest. Studies have shown that there is rapid increase in functional residual capacity after natural surfactant and a less dramatic rise in effective pulmonary blood flow. These changes in blood flow are not associated with a sustained fall in pulmonary artery flow or pressure indicating that the main improvement in oxygenation results from a reduction in intrapulmonary shunting. Recent studies have shown that natural surfactant does produce rapid increases in lung compliance but only if the expired gases are vented to ambient rather than to positive end expiratory pressures. Thus the mechanical effects of natural surfactant are initially largely limited to the part of the tidal volume which is close to the functional residual capacity.

Pulmonary surfactant and COVID-19: A new synthesis

“…In fact, COVID-19 itself, as a natural experiment in physiology, is one of many such bodies of fact, which strongly suggest that not only is pulmonary surfactant (PS) principally involved in gas exchange but also when selectively damaged by SARS-CoV-2, defective PS produces the very unusual clinical syndrome of hypoxemia with normal lung mechanics – the COVID anomaly so often misattributed to defective vascular mechanisms (Gattinoni et al , 2020 b ). We review above the other bodies of fact implicating PS in gas exchange including: (1) cryo-TEM images of alveolar surface layer contradicting the assumption that PS exists as a monolayer and revealing a non-Euclidean 3D structure known as crossed layers of parallel (CLP) (Andersson et al , 1999 ; Larsson et al , 1999 , 2002 ; Larsson and Larsson, 2014 ), (2) the chronology of re-oxygenation of premature infants when treated with PS clearly shows that oxygenation improves in minutes, while compliance, if abnormal at all, improves slowly over 24 h (Milner, 1995 , 1996 ), (3) PS in deepest diving seals does NOT lower surface tension of water at all, and often raises it (Spragg et al , 2004 ; Meir et al , 2009 ), (4) animal experiments in which PS is insufflated via endotracheal tube shows that PS often raises surface tension of alveoli (Nguyen and Perlman, 2018 ), (5) when adult patients with ARDS are treated with PS, oxygenation often improves rapidly, but surface tension lowering may occur only to a minimal degree (Markart et al , 2007 ), and (6) early trials of PS in advanced COVID-19 have produced promising results (Bhatt et al , 2021 ).…”

“…It is a fact that premature infants have underdeveloped lungs with insufficient surfactant production (Comroe, 1977 c ). However, although the success of surfactant treatment for preemies has often been construed as the ultimate verification of the traditional surface tension-lowering theory (Hills, 1999 ), the actual results of the clinical studies flatly contradict that theory, in that: 1) surfactant treatment of NRDS improves oxygenation and Functional Residual Capacity (FRC) long before compliance, and 2) hypoxemic NRDS patients usually have fairly normal compliance to begin with (Milner, 1995 ; Koumbourlis and Motoyama, 2020 ).…”

“…Surfactant may mainly increase the FRC and this would ‘tend to reduce intrapulmonary shunting and might improve ventilation/perfusion ratios. It might even diminish extrapulmonary shunts if there was a direct or indirect effect on the pulmonary artery pressure’ (Milner, 1995 ). Milner’s ad hoc hypotheses attempting to explain how surfactant might operate through traditional vascular physiological and respiratory physical-chemical mechanisms are mirrored in current attempts to explain COVID-19 hypoxemia with preserved lung mechanics in similar fashion, as due to vascular and not alveolar damage (Gattinoni et al , 2020 a ;Lang et al , 2020 ; Solaimanzadeh, 2020 ) (although the possibility of early alveolar damage is certainly suggested by damaged diffusing capacity in recovered COVID-19 patients) (Fuschillo et al , 2021 ).…”

“…Although those authors noting the delay in expected improvement in compliance did not claim that surfactant has no role in surface-tension-lowering and improved compliance, they did ask ‘How does exogenous surfactant really work?’ (Milner, 1993 , 1995 ) It is certainly true that, in many early publications about NRDS, the lungs of premature infants are often described as ‘stiff’, requiring high pressures to inflate (Avery and Mead, 1959 ; Gribetz et al , 1959 ). Laboratory studies of surface tension of bits of minced lung taken from preemies at autopsy using Wilhelmy balance and other older methods suggested that surface tension was indeed higher in preemies than in normal infants (Avery and Mead, 1959 ).…”