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The Perinatal Asphyxiated Lamb Model: A Model for Newborn Resuscitation

Birth asphyxia accounts for nearly one million deaths worldwide each year, and is one of the primary causes of early neonatal morbidity and mortality. ...

University at Buffalo

An increase in oxygen tension is an important factor in decreasing pulmonary vascular resistance (PVR) at birth. Birth asphyxia results in acidosis and increased PVR. We determined the effect of resuscitation with 21 vs. 100% O(2) on pulmonary hemodynamics, pulmonary arterial (PA) reactivity, and oxidant stress in a lamb model of in utero asphyxia. Term fetal lambs were acutely asphyxiated by intrauterine umbilical cord occlusion for 10 min resulting in acidosis (pH 6.96 ± 0.05 and Pco(2) 103 ± 5 Torr), bradycardia, systemic hypotension, and increased PVR. Lambs were treated with 30 min of resuscitation with 21% or 100% O(2) (n = 6 each). Pa(O(2)) was significantly elevated with 100% O(2) resuscitation compared with 21% O(2) (430 ± 38 vs. 64 ± 8 Torr), but changes in pH and Pa(CO(2)) were similar. The 100% O(2) induced greater increase in pulmonary blood flow and decrease in PVR at 1 min of life, but subsequent values were similar to 21% O(2) group between 2 and 30 min of life. Oxygen uptake from the lung and systemic oxygen extraction was similar between the two groups. Pulmonary arteries showed increased staining for superoxide anions and increased contractility to norepinephrine following resuscitation with 100% O(2). The increased PA contractility induced by 100% O(2) was reversed by scavenging superoxide anions with superoxide dismutase and catalase. We conclude that resuscitation of asphyxiated lambs with 100% O(2) increases Pa(O(2)) but does not improve lung oxygen uptake, decrease PVR at 30 min, or increase systemic oxygen extraction ratios. Furthermore, 100% O(2) also induces oxidative stress and increases PA contractility. These findings support the new neonatal resuscitation guidelines recommending 21% O(2) for initial resuscitation of asphyxiated neonates.

Pulmonary hemodynamics and vascular reactivity in asphyxiated term lambs resuscitated with 21 and 100% oxygen.

Current neonatal resuscitation guidelines recommend tracheal suctioning of nonvigorous neonates born through meconium-stained amniotic fluid.

Tracheal suctioning improves gas exchange but not hemodynamics in asphyxiated lambs with meconium aspiration.

The oxygenation index (OI = mean airway pressure, MAP × FiO2 × 100 : PaO2) is used to assess the severity of hypoxic respiratory failure (HRF) and persistent pulmonary hypertension of the newborn (PPHN). An indwelling arterial line or arterial punctures are necessary to obtain PaO2 for the calculation of OI. Oxygenation can be continuously and noninvasively assessed using pulse oximetry. The use of the oxygen saturation index (OSI = MAP × FiO2 × 100 : SpO2) can be an alternate method of assessing the severity of HRF.

Oxygen saturation index and severity of hypoxic respiratory failure.

Intestinal circulation and mesenteric arterial (MA) reactivity may play a role in preparing the fetus for enteral nutrition. We hypothesized that MA vasoreactivity changes with gestation and vasodilator pathways predominate in the postnatal period.

Fetal and postnatal ovine mesenteric vascular reactivity.

The Neonatal Resuscitation Program (NRP) recommends upper and lower limits of preductal saturations (SpO2) extrapolated from studies in infants resuscitated in room air. These limits have not been validated in asphyxia and lung disease.

Neonatal resuscitation adhering to oxygen saturation guidelines in asphyxiated lambs with meconium aspiration.

The Neonatal Resuscitation Program (NRP) recommends close monitoring of oxygenation during the resuscitation of newborns using a pulse oximeter. However, there are no guidelines for monitoring carbon dioxide (CO2) to assess ventilation. Considering that cerebral blood flow (CBF) correlates directly with PaCO2, continuous capnography monitoring of end-tidal CO2 (ETCO2) may limit fluctuations in PaCO2 and, therefore, CBF during resuscitation of asphyxiated infants.

Continuous End-Tidal Carbon Dioxide Monitoring during Resuscitation of Asphyxiated Term Lambs.

Hypernatremia Management: Focus on Etiology.

In neonates requiring chest compression (CC) during resuscitation, neonatal resuscitation program (NRP) recommends against relying on a single feedback device such as end-tidal carbon dioxide (ETCO) or saturations (SpO) to determine return of spontaneous circulation (ROSC) until more evidence becomes available.

Continuous capnography monitoring during resuscitation in a transitional large mammalian model of asphyxial cardiac arrest.

Neonatal liver failure (NLF) is a rare diagnosis but carries with it significant risks of mortality and morbidity. Common etiologies for NLF include metabolic causes, gestational alloimmune liver disease (GALD or neonatal hemochromatosis), and viral infections. We report a case of liver failure in a premature infant with abnormal iron profile within 48 hours of birth. Lack of accepted guidelines for the initial management of severe jaundice with a high direct component in the first week after birth made treatment challenging. The infant underwent intensive phototherapy along with four exchange transfusions (ET) and two courses of intravenous immunoglobulins (IVIG). The clinical goals were to keep total bilirubin values ≤ 20 mg/dL in this premature neonate and to minimize the risk of bilirubin-induced neurologic dysfunction and decompensated liver failure. Abnormal iron studies and later magnetic resonance imaging were suggestive of GALD. Liver functions improved over time with normal neurodevelopmental assessment at 3 years of age. To conclude, in infants with NLF soon after birth, earlier consideration of IVIG/ET in the first few days may be beneficial. Larger multicenter data analyses are required to formulate treatment guidelines and indications for phototherapy, ET, and IVIG in sick neonates with NLF.

Liver Failure and Conjugated Hyperbilirubinemia in a Preterm Neonate: Role of Early IVIG and Exchange Transfusion.

The Neonatal Resuscitation Program recommends initial resuscitation of preterm infants with low oxygen (O) followed by titration to target preductal saturations (SpO). We studied the effect of resuscitation with titrated O on gas exchange, pulmonary, and systemic hemodynamics.

Effect of various inspired oxygen concentrations on pulmonary and systemic hemodynamics and oxygenation during resuscitation in a transitioning preterm model.

Neonatal hypoxic ischemic encephalopathy (HIE) presents a significant clinical burden with its high mortality and morbidity rates globally. Therapeutic hypothermia (TH) is now standard of care for infants with moderate to severe HIE, but has not definitively changed outcomes in severe HIE. In this review, we discuss newer promising markers that may help the clinician identify severity of HIE. Therapies that are beneficial and agents that hold promise for neuroprotection are described, both for use either alone or as adjuncts to TH. These include endogenous pathway modifiers such as erythropoietin and analogues, melatonin, and remote ischemic post conditioning. Stem cells have therapeutic potential in this condition, as in many other neonatal conditions. Of the agents listed, only erythropoietin and analogues are currently being evaluated in large randomized controlled trials (RCTs). Exogenous therapies such as argon and xenon, allopurinol, monosialogangliosides, and magnesium sulfate continue to be investigated. The recognition of tertiary mechanisms of brain damage has opened up new research into therapies not only to attenuate brain damage but also to promote cell repair and regeneration in a developmentally disorganized brain long after the perinatal insult. These alternative modalities may be especially important in mild HIE and in areas of the world where there is limited access to expensive hypothermia equipment and services.

Article	Year
Pulmonary hemodynamics and vascular reactivity in asphyxiated term lambs resuscitated with 21 and 100% oxygen. Journal of applied physiology (Bethesda, Md. : 1985)\| PubMed ID: 21799125	2011
Tracheal suctioning improves gas exchange but not hemodynamics in asphyxiated lambs with meconium aspiration. Pediatric research\| PubMed ID: 25406897	2015
Oxygen saturation index and severity of hypoxic respiratory failure. Neonatology\| PubMed ID: 25592054	2015
Fetal and postnatal ovine mesenteric vascular reactivity. Pediatric research\| PubMed ID: 26672733	2016
Neonatal resuscitation adhering to oxygen saturation guidelines in asphyxiated lambs with meconium aspiration. Pediatric research\| PubMed ID: 26672734	2016
Continuous End-Tidal Carbon Dioxide Monitoring during Resuscitation of Asphyxiated Term Lambs. Neonatology\| PubMed ID: 26866711	2016
Hypernatremia Management: Focus on Etiology. Clinical pediatrics\| PubMed ID: 28056559	2018
Continuous capnography monitoring during resuscitation in a transitional large mammalian model of asphyxial cardiac arrest. Pediatric research\| PubMed ID: 28157836	2017
Liver Failure and Conjugated Hyperbilirubinemia in a Preterm Neonate: Role of Early IVIG and Exchange Transfusion. AJP reports\| PubMed ID: 29765787	2018
Effect of various inspired oxygen concentrations on pulmonary and systemic hemodynamics and oxygenation during resuscitation in a transitioning preterm model. Pediatric research\| PubMed ID: 29967523	2018
Current and Emerging Therapies in the Management of Hypoxic Ischemic Encephalopathy in Neonates. Children (Basel, Switzerland)\| PubMed ID: 30029531	2018

Jayasree Nair

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