Abstract
Preterm infants are at high risk of death and disability resulting from brain injury. Impaired cardiovascular function leading to poor cerebral oxygenation is a significant contributor to these adverse outcomes, but current therapeutic approaches have failed to improve outcome. We have re-examined existing evidence regarding hypovolemia and have concluded that in the preterm infant loss of plasma from the circulation results in hypovolemia; and that this is a significant driver of cardiovascular instability and thus poor cerebral oxygenation. High capillary permeability, altered hydrostatic and oncotic pressure gradients, and reduced lymphatic return all combine to increase net loss of plasma from the circulation at the capillary. Evidence is presented that early hypovolemia occurs in preterm infants, and that capillary permeability and pressure gradients all change in a way that promotes rapid plasma loss at the capillary. Impaired lymph flow, inflammation and some current treatment strategies may further exacerbate this plasma loss. A framework for testing this hypothesis is presented. Understanding these mechanisms opens the way to novel treatment strategies to support cardiovascular function and cerebral oxygenation, to replace current therapies, which have been shown not to change outcomes.
Highlights
Preterm infants are at high risk of poor neurodevelopmental outcome
In the preterm infant, high capillary permeability, altered hydrostatic and oncotic pressure gradients, and reduced lymphatic return all combine to increase net loss of plasma from the circulation, resulting in hypovolemia; and that this is a significant driver of cardiovascular instability and poor cerebral oxygenation
Preterm neonates have impaired postnatal lymphatic flow. All of these factors would contribute to plasma volume loss resulting in hypotension, and reduced cerebral blood flow and oxygenation in preterm infants
Summary
Preterm infants are at high risk of poor neurodevelopmental outcome. Survival rates of preterm infants have improved with modern care, such that in a recent study across 10 neonatal networks 87% of infants born at 24–30 wk survived [1]. In the preterm infant, high capillary permeability, altered hydrostatic and oncotic pressure gradients, and reduced lymphatic return all combine to increase net loss of plasma from the circulation, resulting in hypovolemia; and that this is a significant driver of cardiovascular instability and poor cerebral oxygenation. Even small changes in the system (e.g., increased capillary permeability, low oncotic pressure, increased hydrostatic pressure gradient or reduced lymph flow) will result in loss of plasma from the circulation (Figure 3). This reduction in blood pressure may be due to an increase in driving pressure produced by dopamine leading to an increase in the hydrostatic pressure gradient across the capillary and plasma loss It needs to be determined if this partly explains why dopamine and dobutamine are ineffective for improving outcomes [9] and why “permissive hypotension” does not result in worse outcomes [67]. Animal experiments designed to test if either elevated intrathoracic pressure or inflammation limits lymphatic flow are necessary to determine if tissue clearance of fluid is compromised
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