Multimodal Monitoring of Hemodynamics in Extremely Low Birth Weight Preterm Infant in a Canadian Tertiary Level Unit- Non-Blinded Randomized Control Trial

Background:

Neonatal transition from the intra-uterine to extra-uterine environment is a complex, multi-organ process. The heart of a term neonate is anatomically and functionally mature to make the transition. However, the feto-neonatal transition of Extremely Low Gestational Age Neonates (ELGAN) may have significant challenges in the context of the physiologically "less than adequate" myocardial function and a delicate balance between pulmonary and systemic blood flow. Further, the brain and cerebrovascular state of ELGAN are particularly vulnerable to the effects of an unbalanced transition. Despite advances in neonatal intensive care that have contributed to a decline in mortality and morbidity, preterm birth remains a major cause of mortality and long term neurological sequelae. Brain injury in preterm infants is often caused by disturbances in cerebral blood flow (CBF) and oxygenation that happen early in the transition when the majority of intraventricular bleeds and parenchymal infarcts occur. Therefore, it is important to evaluate the systemic and regional hemodynamic state of ELGAN in order to facilitate the neonatal transition.

Neonatal clinicians assess the hemodynamic status of the infant using clinical signs and physiological parameters including heart rate, blood pressure, capillary refill time, urine output and laboratory parameters (base deficit and lactate). While urine output and laboratory parameters do not provide real-time assessment of the hemodynamic status, heart rate and capillary refill time could be non-specific, inaccurate and observer-dependent, respectively. Blood pressure continues to be used as a common physiological marker for cardiovascular state in neonates. However, there is increasing amount of evidence that monitoring blood pressure alone is not enough to ensure adequate systemic and cerebral perfusion and oxygenation. Indeed, preterm babies may have "low blood pressure" triggering pharmacological treatment while still maintaining adequate systemic flow- especially cerebral and other organ perfusion as shown by other noninvasive measures like targeted neonatal echocardiography (TNE) and near infrared spectroscopy (NIRS). Interestingly, studies have demonstrated that independent of early blood pressure changes, anti-hypotensive therapy exposure in ELGAN was associated with an increased risk of death/NIDD at 18-22 months' corrected age even after controlling for risk factors known to affect survival and neurodevelopment.

The use of targeted neonatal echocardiography (TNE) by neonatal clinicians to evaluate cardiovascular state in neonates is common in many tertiary neonatal intensive care units. When used in combination with clinical findings, neonatal echocardiography may be an invaluable tool for the identification of hemodynamic compromise, guiding therapeutic intervention, and monitoring treatment response. There are an increasing number of prospective studies that highlight the potential merits of TNE in identification of cardiovascular compromise and guiding neonatal cardiovascular care. In addition, it has been shown that the use of early echocardiography to provide targeted PDA treatment may result in a reduction of severe intraventricular hemorrhage and pulmonary hemorrhages. The role of TNE to study organ blood flow including cerebral, renal and the gut is largely limited.

Near-infrared spectroscopy (NIRS) is a technique that can be used to monitor regional cerebral oxygen saturation (rScO2), being both a measure of cerebral oxygenation as well as a surrogate of cerebral blood flow. NIRS monitoring can be applied for prolonged periods of time, even in the most vulnerable infants. It uses multiple wavelengths of NIR light and relies on the distinct absorption spectra of oxygenated (O2Hb) and deoxygenated. NIRS offers the ability to assess target organ blood flow. It offers additional information regarding organ perfusion, which supplements data provided by echocardiography and other modalities. In preterm infants, NIRS-derived fractional tissue oxygen extraction and regional cerebral oxygen saturation reference values, particularly over the first 72 hours of life, are emerging. NIRS is being used in many centers including ours, in an ad-hoc manner. In a multicenter, randomized, controlled trial, infants monitored with NIRS and treated for evolving cerebral hypoxia had a lower cerebral hypoxic burden when compared with infants who were not treated based on NIRS findings. The long-term benefit of this approach has yet to be elucidated.