The Daily Dose • Tuesday, May 1

Blue Babies: How Do They Survive?

By Dr. Linda Trapani, from the IARS 2018 Annual Meeting*

Neonatal cyanosis can be caused by a host of factors, most related to lesions of the cardiopulmonary system–and are a fairly common challenge for the pediatric anesthesiologist. Dr. Minal J. Menezes’ study of nitric oxide’s role in allowing cyanotic babies to adapt to their physiological challenges may give us the tools to improve the care of children enduring significant perioperative issues.

While cyanosis in the newborn can be an alarming symptom, the majority of these children are able to survive in their early life. Further, many of them are subjected to stressful, staged procedures to repair or palliate their underlying issue – only underscoring the adaptive capabilities of our smallest patients. How do they do it? As it turns out, a variety of mechanisms allow babies to exist at low oxygen saturations. From a metabolic perspective, these children perform more of their functions using anaerobic metabolism, thus reducing the amount of oxygen required for energy production. While this raises other metabolic consequences, it represents a stop-gap means of energy production. Babies forced into this state also seem to express a variety of hypoxia-inducible factors (HIFs), transcription factors that promote angiogenesis and other regenerative processes that allow growth in spite of low oxygen conditions.

From a pulmonary perspective, hypoxemia can influence alveolar density within the lung. And as we are all familiar with as anesthesia providers, hypoxic pulmonary vasoconstriction drives blood to optimally-oxygenated lung tissue to maximize efficient oxygen uptake.

Hemoglobin’s ability to respond to low oxygen conditions represents another important adaptation–changes in oxygen tension, carbon dioxide and acid levels all influence the ability of hemoglobin to “pick up” and “drop off” oxygen.

Cardiovascular adaptations include changes in cardiac output (which, in neonates, is achieved primarily through changes in heart rate) and changes in regional blood flow. These regional changes are achieved largely through the action of nitric oxide.

Nitric oxide, or NO, isn’t a new agent when it comes to cardiovascular care. Since the late 1800s it has been identified as a treatment for angina pectoris and was even named “Molecule of the Year” in 1992 when it was the topic of a Nobel Prize win. This small molecule makes a major contribution to changes in vascular tone; its cyclic generation relies on the action of nitric oxide synthase (NOS) on L-arginine. In hypoxic states, NO is generated; in oxygen-rich states, it is oxidized to generate nitrite and nitrate.

NO has long been a treatment option in persistent pulmonary hypertension, both in the pediatric and adult populations. Presently, research is focusing on its potential benefits to babies with other cardiopulmonary lesions, specifically those undergoing the stress of cardiopulmonary bypass during their surgeries.

Emerging research is revealing, objectively, that NO may benefit neonates undergoing CPB. In a study where NO was bled into the CPB circuit, allowing the provision of the molecule during the pump run, those patients receiving NO had a significant reduction in their number of ventilator-dependent days. Further, their overall ICU length of stay was shorter, suggesting a global improvement in their condition (not simply from a pulmonary perspective). Moreover, these patients exhibited reduced incidence of low cardiac output syndrome, an imbalance of oxygen delivery and demand resulting in metabolic acidosis; patients typically display a cardiac index of less than 2 L/min/m2, and a systolic blood pressure of less than 90 mmHg along with subjective evidence of hypoperfusion (cold extremities, clammy skin, oliguria) in the absence of hypovolemia. On a tissue level, neonates in the treatment group had lower levels of troponin and BNP in their blood, suggesting less cardiac damage, and less congestion from poor cardiac function.

New tools are now making NO’s effects at the vascular level visible instantly, in vivo. Using sidestream dark field microscopy, researchers have been able to quantify the vessel-level effects of NO on these infants. The treatment group had improved vessel density, an increased percentage of those vessels perfused, and an overall increase in their microvascular flow index– a measure of the quality of perfusion. This technology thus provides live, local analysis of microvasculature, a likely site of NO exertion of its protective effects.

Future directions for research with NO include optimizing its levels within CPB patients via nutrition, direct administration and utilization of pharmacotherapy. Further, researchers hope this work is generalizable to older children and adults.

Though the medical community has long known about the existence of NO and some of its contributions to normal physiology, it seems we are just beginning to scratch the surface of its potential in treatment of our youngest, sickest patients undergoing major cardiovascular surgery.

*Coverage of the Review Course Lecture, Blue Babies: How Do They Survive?