Supplemental Oxygen in the Newborn: Historical Perspective and Current Trends

Oxygen is the final electron acceptor in aerobic respiration, and a lack of oxygen can result in bioenergetic failure and cell death. Thus, administration of supplemental concentrations of oxygen to overcome barriers to tissue oxygen delivery (e.g., heart failure, lung disease, ischemia), can rescue dying cells where cellular oxygen content is low. However, the balance of oxygen delivery and oxygen consumption relies on tightly controlled oxygen gradients and compartmentalized redox potential. While therapeutic oxygen delivery can be life-saving, it can disrupt growth and development, impair bioenergetic function, and induce inflammation. Newborns, and premature newborns especially, have features that confer particular susceptibility to hyperoxic injury due to oxidative stress. In this review, we will describe the unique features of newborn redox physiology and antioxidant defenses, the history of therapeutic oxygen use in this population and its role in disease, and clinical trends in the use of therapeutic oxygen and mitigation of neonatal oxidative injury.

Clinical Application of the Fluid Challenge Approach in Goal-Directed Fluid Therapy: What Can We Learn From Human Studies?

Resuscitative fluid therapy aims to increase stroke volume (SV) and cardiac output (CO) and restore/improve tissue oxygen delivery in patients with circulatory failure. In individualized goal-directed fluid therapy (GDFT), fluids are titrated based on the assessment of responsiveness status (i.e., the ability of an individual to increase SV and CO in response to volume expansion). Fluid administration may increase venous return, SV and CO, but these effects may not be predictable in the clinical setting. The fluid challenge (FC) approach, which consists on the intravenous administration of small aliquots of fluids, over a relatively short period of time, to test if a patient has a preload reserve (i.e., the relative position on the Frank-Starling curve), has been used to guide fluid administration in critically ill humans. In responders to volume expansion (defined as individuals where SV or CO increases ≥10–15% from pre FC values), FC administration is repeated until the individual no longer presents a preload reserve (i.e., until increases in SV or CO are <10–15% from values preceding each FC) or until other signs of shock are resolved (e.g., hypotension). Even with the most recent technological developments, reliable and practical measurement of the response variable (SV or CO changes induced by a FC) has posed a challenge in GDFT. Among the methods used to evaluate fluid responsiveness in the human medical field, measurement of aortic flow velocity time integral by point-of-care echocardiography has been implemented as a surrogate of SV changes induced by a FC and seems a promising non-invasive tool to guide FC administration in animals with signs of circulatory failure. This narrative review discusses the development of GDFT based on the FC approach and the response variables used to assess fluid responsiveness status in humans and animals, aiming to open new perspectives on the application of this concept to the veterinary field.

Brain Protection after Anoxic Brain Injury: Is Lactate Supplementation Helpful?

While sudden loss of perfusion is responsible for ischemia, failure to supply the required amount of oxygen to the tissues is defined as hypoxia. Among several pathological conditions that can impair brain perfusion and oxygenation, cardiocirculatory arrest is characterized by a complete loss of perfusion to the brain, determining a whole brain ischemic-anoxic injury. Differently from other threatening situations of reduced cerebral perfusion, i.e., caused by increased intracranial pressure or circulatory shock, resuscitated patients after a cardiac arrest experience a sudden restoration of cerebral blood flow and are exposed to a massive reperfusion injury, which could significantly alter cellular metabolism. Current evidence suggests that cell populations in the central nervous system might use alternative metabolic pathways to glucose and that neurons may rely on a lactate-centered metabolism. Indeed, lactate does not require adenosine triphosphate (ATP) to be oxidated and it could therefore serve as an alternative substrate in condition of depleted energy reserves, i.e., reperfusion injury, even in presence of adequate tissue oxygen delivery. Lactate enriched solutions were studied in recent years in healthy subjects, acute heart failure, and severe traumatic brain injured patients, showing possible benefits that extend beyond the role as alternative energetic substrates. In this manuscript, we addressed some key aspects of the cellular metabolic derangements occurring after cerebral ischemia-reperfusion injury and examined the possible rationale for the administration of lactate enriched solutions in resuscitated patients after cardiac arrest.

Systems Biology Model of Cerebral Oxygen Delivery and Metabolism During Therapeutic Hypothermia: Application to the Piglet Model

Hypoxic ischaemic encephalopathy (HIE) is a significant cause of death and disability. Therapeutic hypothermia (TH) is the only available standard of treatment, but 45–55% of cases still result in death or neurodevelopmental disability following TH. This work has focussed on developing a new brain tissue physiology and biochemistry systems biology model that includes temperature effects, as well as a Bayesian framework for analysis of model parameter estimation. Through this, we can simulate the effects of temperature on brain tissue oxygen delivery and metabolism, as well as analyse clinical and experimental data to identify mechanisms to explain differing behaviour and outcome. Presented here is an application of the model to data from two piglets treated with TH following hypoxic-ischaemic injury showing different responses and outcome following treatment. We identify the main mechanism for this difference as the Q10 temperature coefficient for metabolic reactions, with the severely injured piglet having a median posterior value of 0.133 as opposed to the mild injury value of 5.48. This work demonstrates the use of systems biology models to investigate underlying mechanisms behind the varying response to hypothermic treatment.

Erythropoiesis

Erythropoiesis is a highly regulated, multistep process in which stem cells, after a series of amplification divisions, generate multipotential progenitor cells, then oligo- and finally unilineage erythroid progenitors, and then morphologically recognizable erythroid precursors and mature red cells. The ontogeny of erythropoiesis involves a series of well-coordinated events during embryonic and early fetal life. In the fetus, the main site of erythropoiesis is the liver, which initially produces mainly fetal haemoglobin (HbF, α‎2γ‎2) and a small component (10–15%) of adult haemoglobin (HbA, α‎2β‎2), with the fraction of HbA rising to about 50% at birth. After birth, the site of erythroid cell production maintained throughout life is the bone marrow, with the final adult erythroid pattern (adult Hb with <1% fetal Hb) being reached a few months after birth. Regulation of erythropoiesis—the main regulator is erythropoietin, a sialoglycoprotein that is produced by interstitial cells in the kidney in response to tissue hypoxia and exerts its effect by binding to a specific receptor on erythroid burst-forming units, erythroid colony-forming units, and proerythroblasts. Abnormal erythropoietin production—anaemia can be caused by acquired or congenital deficiency in erythropoietin production, most commonly in chronic kidney disease. Impaired tissue oxygen delivery is a common cause of erythropoietin-driven secondary erythrocytosis. Some kidney cancers increase erythropoietin production and hence cause secondary erythrocytosis. Other causes of abnormal erythroid production include (1) acquired and congenital defects in erythropoietin signalling; (2) acquired and congenital defects in the transcription factors GATA1 or EKLF; (3) acquired or congenital abnormalities in ribosome synthesis or splicing factors; and (4) factors that lead to premature red cell destruction.

The Use of Data Science to Analyse Physiology of Oxygen Delivery in the Extracorporeal Circulation

Background Recent scientific reports have brought into light a new concept of goal-directed perfusion (GDP) that aims to recreate physiological conditions in which the risk of end-organ malperfusion is minimalized. The aim of our study was to analyse patients’ interim physiology while on cardiopulmonary bypass based on the haemodynamic and tissue oxygen delivery measurements. We also aimed to create a universal formula that may help in further implementation of the GDP concept. Methods We retrospectively analysed patients operated on at the Wroclaw University Hospital between June 2017 and December 2018. Since our observations provided an extensive amount of data, including the patients' demographics, surgery details and the perfusion-related data, the Data Science methodology was applied. Results A total of 272 (mean age 62.5±12.4, 74% male) cardiac surgery patients were included in the study. To study the relationship between haemodynamic and tissue oxygen parameters, the data for three different values of DO2i (280 ml/min/m2, 330 ml/min/m2 and 380ml/min/m2), were evaluated. Each set of those lines showed a descending function of CI in Hb concentration for the set DO2i. Conclusions Modern calculation tools make it possible to create a common data platform from a very large database. Using that methodology we created models of haemodynamic compounds describing tissue oxygen delivery. The obtained unique patterns may both allow the adaptation of the flow in relation to the patient’s unique morphology that changes in time and contribute to wider and safer implementation of perfusion strategy which has been tailored to every patient’s individual needs.

Cremaster muscle perfusion, oxygenation, and heterogeneity revealed by a new automated acquisition system in a rodent model of prolonged hemorrhagic shock

Local blood flow/oxygen partial pressure (Po2) distributions and flow-Po2 relationships are physiologically relevant. They affect the pathophysiology and treatment of conditions like hemorrhagic shock (HS), but direct noninvasive measures of flow, Po2, and their heterogeneity during prolonged HS are infrequently presented. To fill this void, we report the first quantitative evaluation of flow-Po2 relationships and heterogeneities in normovolemia and during several hours of HS using noninvasive, unbiased, automated acquisition. Anesthetized rats were subjected to tracheostomy, arterial/venous catheterizations, cremaster muscle exteriorization, hemorrhage (40% total blood volume), and laparotomy. Control animals equally instrumented were not subjected to hemorrhage/laparotomy. Every 0.5 h for 4.5 h, noninvasive laser speckle contrast imaging and phosphorescence quenching were employed for nearly 7,000 flow/Po2 measurements in muscles from eight animals, using an automated system. Precise alignment of 16 muscle areas allowed overlapping between flow and oxygenation measurements to evaluate spatial heterogeneity, and repeated measurements were used to estimate temporal heterogeneity. Systemic physiological parameters and blood chemistry were simultaneously assessed by blood samplings replaced with crystalloids. Hemodilution was associated with local hypoxia, but increased flow prevented major oxygen delivery decline. Adding laparotomy and prolonged HS resulted in hypoxia, ischemia, decreased tissue oxygen delivery, and logarithmic flow/Po2 relationships in most regions. Flow and Po2 spatial heterogeneities were higher than their respective temporal heterogeneities, although this did not change significantly over the studied period. This quantitative framework establishes a basis for evaluating therapies aimed at restoring muscle homeostasis, positively impacting outcomes of civilian and military trauma/HS victims. NEW & NOTEWORTHY This is the first study on flow-Po2 relationships during normovolemia, hemodilution, and prolonged hemorrhagic shock using noninvasive methods in multiple skeletal muscle areas of monitored animals. Automated flow/Po2 measurements revealed temporal/spatial heterogeneities, hypoxia, ischemia, and decreased tissue oxygen delivery after trauma/severe hemorrhage. Hemodilution was associated with local hypoxia, but hyperemia prevented a major decline in oxygen delivery. This framework provides a quantitative basis for testing therapeutics that positively impacts muscle homeostasis and outcomes of trauma/hemorrhagic shock victims.

The use of data science to analyse physiology of oxygen delivery in the extracorporeal circulation

Background Recent scientific reports have brought into light a new concept of goal-directed perfusion (GDP) that aims to recreate physiological conditions in which the risk of end-organ malperfusion is minimalized. The aim of our study was to analyse patients’ interim physiology while on cardiopulmonary bypass based on the haemodynamic and tissue oxygen delivery measurements. We also aimed to create a universal formula that may help in further implementation of the GDP concept. Methods We retrospectively analysed patients operated on at the Wroclaw University Hospital between June 2017 and December 2018. Since our observations provided an extensive amount of data, including the patients’ demographics, surgery details and the perfusion-related data, the Data Science methodology was applied. Results A total of 272 (mean age 62.5 ± 12.4, 74% male) cardiac surgery patients were included in the study. To study the relationship between haemodynamic and tissue oxygen parameters, the data for three different values of DO2i (280 ml/min/m2, 330 ml/min/m2 and 380 ml/min/m2), were evaluated. Each set of those lines showed a descending function of CI in Hb concentration for the set DO2i. Conclusions Modern calculation tools make it possible to create a common data platform from a very large database. Using that methodology we created models of haemodynamic compounds describing tissue oxygen delivery. The obtained unique patterns may both allow the adaptation of the flow in relation to the patient’s unique morphology that changes in time and contribute to wider and safer implementation of perfusion strategy which has been tailored to every patient’s individual needs.