Shannon E. G. Hamrick

Patent Ductus Arteriosus of the Preterm Infant

A persistently patent ductus arteriosus (PDA) in preterm infants can have significant clinical consequences, particularly during the recovery period from respiratory distress syndrome. With improvement of ventilation and oxygenation, the pulmonary vascular resistance decreases early and rapidly, especially in very immature infants with extremely low birth weight (<1000 g). Subsequently, the left-to-right shunt through the ductus arteriosus (DA) is augmented, thereby increasing pulmonary blood flow, which leads to pulmonary edema and overall worsening of cardiopulmonary status. Prolonged ventilation, with the potential risks of volutrauma, barotrauma, and hyperoxygenation, is strongly associated with the development and severity of bronchopulmonary dysplasia/chronic lung disease. Substantial left-to-right shunting through the ductus may also increase the risk of intraventricular hemorrhage, necrotizing enterocolitis, and death. Postnatal ductal closure is regulated by exposure to oxygen and vasodilators; the ensuing vascular responses, mediated by potassium channels, voltage-gated calcium channels, mitochondrial-derived reactive oxygen species, and endothelin 1, depend on gestational age. Platelets are recruited to the luminal aspect of the DA during closure and probably promote thrombotic sealing of the constricted DA. Currently, it is unclear whether and when a conservative, pharmacologic, or surgical approach for PDA closure may be advantageous. Furthermore, it is unknown if prophylactic and/or symptomatic PDA therapy will cause substantive improvements in outcome. In this article we review the mechanisms underlying DA closure, risk factors and comorbidities of significant DA shunting, and current clinical evidence and areas of uncertainty in the diagnosis and treatment of PDA of the preterm infant.

Temporal and Anatomic Risk Profile of Brain Injury With Neonatal Repair of Congenital Heart Defects

Background and Purpose— Brain injury is common in newborns with congenital heart disease (CHD) requiring neonatal surgery. The purpose of this study is to define the risk factors for preoperative and postoperative brain injuries and their association with functional cardiac anatomic groups. Methods— Sixty-two neonates with CHD were studied with preoperative MRI, and 53 received postoperative scans. Clinical and therapeutic characteristics were compared in newborns with and without newly acquired brain injuries. A subset of 16 consecutive patients was monitored with intraoperative cerebral near-infrared spectroscopy. Results— Brain injury was observed in 56% of patients. Preoperative brain injury, seen in 39%, was most commonly stroke and was associated with balloon atrial septostomy (P=0.002). Postoperative brain injury, seen in 35%, was most commonly white matter injury and was particularly common in neonates with single-ventricle physiology and aortic arch obstruction (P=0.001). Risk factors associated with acquired postoperative brain injury included cardiopulmonary bypass (CPB) with regional cerebral perfusion (P=0.01) and lower intraoperative cerebral hemoglobin oxygen saturation during the myocardial ischemic period of CPB (P=0.008). In a multivariable model, new postoperative white matter injury was specifically associated with low mean blood pressure during the first postoperative day (P=0.04). Conclusions— Specific modifiable risk factors can be identified for preoperative and postoperative white matter injury and stroke associated with neonatal surgery for CHD. The high incidence of postoperative injury observed despite new methodologies of CPB indicates the need for ongoing evaluation to optimize neurological outcome.

Balloon Atrial Septostomy Is Associated With Preoperative Stroke in Neonates With Transposition of the Great Arteries

Background— Preoperative brain injury is common in neonates with transposition of the great arteries (TGA). The objective of this study is to determine risk factors for preoperative brain injury in neonates with TGA. Methods and Results— Twenty-nine term neonates with TGA were studied with MRI before cardiac surgery in a prospective cohort study. Twelve patients (41%) had brain injury on preoperative MRI, and all injuries were focal or multifocal. None of the patients had birth asphyxia. Nineteen patients (66%) required preoperative balloon atrial septostomy (BAS). All patients with brain injury had BAS (12 of 19; risk difference, 63%; 95% confidence interval, 41 to 85; P=0.001). As expected on the basis of the need for BAS, these neonates had lower systemic arterial hemoglobin saturation (Sao2) (P=0.05). The risk of injury was not modified by the cannulation site for septostomy (umbilical versus femoral, P=0.8) or by the presence of a central venous catheter (P=0.4). Conclusions— BAS is a major identifiable risk factor for preoperative focal brain injury in neonates with TGA. Imaging characteristics of identified brain injuries were consistent with embolism; however, the mechanism is more complex than site of vascular access for BAS or exposure to central venous catheters. These findings have implications for the indications for BAS, timing of surgical repair, and use of anticoagulation in TGA.

Regulation of hypoxia-inducible factor 1α and induction of vascular endothelial growth factor in a rat neonatal stroke model

Stroke is a devastating condition occurring in at least 1 in 4000 live births in the neonatal period. Since hypoxia-inducible factor (HIF)-1alpha can modulate ischemic injury via induction of target genes that may protect cells against ischemia, and is induced after preconditioning by hypoxia in the neonatal rat brain hypoxia-ischemia model, we evaluated whether HIF-1alpha is induced after focal ischemia-reperfusion, a model for neonatal stroke. We developed an ischemia-reperfusion model in postnatal day 10 (P10) rats by transiently occluding the middle cerebral artery (MCA) for 1.5 h. The MCA territory was reperfused for 0, 4, 8, or 24 h and the expression of HIF-1alpha and its target gene, vascular endothelial growth factor (VEGF), were delineated. HIF-1alpha protein and VEGF protein peaked at 8 h, and declined subsequently at 24 h in injured cortex following 1.5 h of MCA occlusion. Double-immunolabeling indicated that both HIF-1alpha and VEGF are expressed together in neurons with a similar time course of expression. The presence of HIF-1alpha and VEGF after moderate ischemia-reperfusion injury suggests potential avenues to exploit for neuroprotection.

Therapeutic hypothermia in neonates. Review of current clinical data, ILCOR recommendations and suggestions for implementation in neonatal intensive care units

Recent evidence suggests that the current ILCOR guidelines regarding hypothermia for the treatment of neonatal encephalopathy need urgent revision. In 2005 when the current ILCOR guidelines were finalised one large (CoolCap trial, n=235) and one small RCT (n=67), in addition to pilot trials, had been published, and demonstrated that therapeutic hypothermia after perinatal asphyxia was safe. The CoolCap trial showed a borderline overall effect on death and disability at 18 months of age, but significant improvement in a large subset of infants with less severe electroencephalographic changes. Based on this and other available evidence, the 2005 ILCOR guidelines supported post-resuscitation hypothermia in paediatric patients after cardiac arrest, but not after neonatal resuscitation. Subsequently, a whole body cooling trial supported by the NICHD reported a significant overall improvement in death or disability. Further large neonatal trials of hypothermia have stopped recruitment and their final results are likely to be published 2009-2011. Many important questions around the optimal therapeutic use of hypothermia remain to be answered. Nevertheless, independent meta-analyses of the published trials now indicate a consistent, robust beneficial effect of therapeutic hypothermia for moderate to severe neonatal encephalopathy, with a mean NNT between 6 and 8. Given that there is currently no other clinically proven treatment for infants with neonatal encephalopathy we propose that an interim advisory statement should be issued to support and guide the introduction of therapeutic hypothermia into routine clinical practice.

Regional and central venous oxygen saturation monitoring following pediatric cardiac surgery: concordance and association with clinical variables.

Objective: To compare changes in regional cerebral or flank oxygen saturation measured by near-infrared spectroscopy with changes in central venous oxygen saturation (Scvo2) and to determine clinical variables associated with these changes. Design: Prospective observational cohort study. Setting: University tertiary care center, pediatric cardiac intensive care unit. Patients: Seventy postoperative congenital cardiac surgical patients (median age 0.3 yrs; interquartile range 0.02–0.46 yrs). Interventions: None. Measurements and Main Results: We measured temporally correlated regional oxygen saturation (rSo2) with hematologic (hematocrit), biochemical (arterial blood gas, Scvo2, and lactate) and physiologic (temperature, heart rate, mean blood pressure, and pulse oximetry) variables in the first postoperative day. Cerebral and flank rSo2 were strongly correlated with Scvo2, in both cyanotic or acyanotic patients and single- or two-ventricle physiology with and without aortic arch obstruction (all p < .001). However, individual values had wide limits of agreement on Bland-Altman analysis. The correlations of change in these measurements were weaker but still significant (all p < .0001), again with wide limits of agreement. Similar direction of change in cerebral rSo2 and Scvo2 was present 64% (95% confidence interval, 55–73%) of the time. Change in arterial pressure of carbon dioxide (&Dgr;Paco2) was associated with cerebral &Dgr;rSo2 (&Dgr;Paco2 &bgr; = 0.35, p < .0001) but not flank &Dgr;rSo2 or &Dgr;Scvo2. A pattern of relative cerebral desaturation (flank rSo2 > cerebral rSo2) was noted in a majority of patients (81%) with two-site monitoring regardless of bypass method or age. Conclusions: Neither individual values nor changes in rSo2 are interchangeable measures of Scvo2 in postoperative pediatric cardiac patients. The unique relationship between changes in Paco2 and cerebral rSo2 supports the hypothesis that cerebral near-infrared spectroscopy monitors regional cerebral oxygenation. Clinical application of this monitor must include recognition of the clinical variables that affect regional brain oxygenation.

Potential for protection and repair following injury to the developing brain: a role for erythropoietin?

Perinatal brain injury is a major contributor to perinatal morbidity and mortality, and a considerable number of these children will develop long term neurodevelopmental disabilities. Despite the severe clinical and socio-economic significance and the advances in neonatal care over the past twenty years, no therapy yet exists that effectively prevents or ameliorates detrimental neurodevelopmental effects in cases of perinatal/neonatal brain injury. Our objective is to review recent evidence in relation to the pervading hypothesis for targeting time-dependent molecular and cellular repair mechanisms in the developing brain. In addition we review several potential neuroprotective strategies specific to the developing nervous system, with a focus on erythropoietin (Epo) because of its potential role in protection as well as repair.

Multiple pathways of neuroprotection against oxidative stress and excitotoxic injury in immature primary hippocampal neurons

In the immature brain hydrogen peroxide accumulates after excitotoxic hypoxia-ischemia and is neurotoxic. Immature hippocampal neurons were exposed to N-methyl-D-aspartate (NMDA), a glutamate agonist, and hydrogen peroxide (H(2)O(2)) and the effects of free radical scavenging and transition metal chelation on neurotoxicity were studied. alpha-Phenyl-N-tert.-butylnitrone (PBN), a known superoxide scavenger, attenuated both H(2)O(2) and NMDA mediated toxicity. Treatment with desferrioxamine (DFX), an iron chelator, at the time of exposure to H(2)O(2) was ineffective, but pretreatment was protective. DFX also protected against NMDA toxicity. TPEN, a metal chelator with higher affinities for a broad spectrum of transition metal ions, also protected against H(2)O(2) toxicity but was ineffective against NMDA induced toxicity. These data suggest that during exposure to free radical and glutamate agonists, the presence of iron and other free metal ions contribute to neuronal cell death. In the immature nervous system this neuronal injury can be attenuated by free radical scavengers and metal chelators.

Treatment of rebound and chronic pulmonary hypertension with oral sildenafil in an infant with congenital diaphragmatic hernia.

Objective We describe a case of chronic pulmonary hypertension in a 7-wk-old infant with congenital diaphragmatic hernia and an oral teratoma. Our patient was dependent on low-dose inhaled nitric oxide and was still very unstable with systemic right ventricular pressures leading to frequent oxygen desaturations. We administered sildenafil therapy to stabilize the infant with discontinuation of inhaled nitric oxide. We describe successful discontinuation of the inhaled therapy as well as a period of stabilization and improvement with continued sildenafil administration. Design Case report. Setting Intensive care nursery in tertiary academic center. Patient A 7-wk-old infant with congenital diaphragmatic hernia who was mechanically ventilated from birth. Intervention Oral sildenafil 0.3 mg/kg/dose every 12 hrs. Measurements and Results Right ventricular pressure (from tricuspid valve regurgitant flow) to systemic systolic arterial pressure was measured by echocardiogram. Right ventricular to systemic pressure ratio was marginally improved with the initiation of sildenafil therapy. Inhaled nitric oxide was successfully discontinued, and the patient clinically stabilized temporarily, but he ultimately succumbed to his pulmonary hypertension. Conclusion Sildenafil may be a useful therapy for chronic pulmonary hypertension in congenital diaphragmatic hernia, but further studies of safety and efficacy need to be performed.

Guidelines for the determination of brain death in infants and children: An update of the 1987 Task Force recommendations

Objective:To review and revise the 1987 pediatric brain death guidelines. Methods:Relevant literature was reviewed. Recommendations were developed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. Conclusions and Recommendations:1) Determination of brain death in term newborns, infants, and children is a clinical diagnosis based on the absence of neurologic function with a known irreversible cause of coma. Because of insufficient data in the literature, recommendations for preterm infants <37 wks gestational age are not included in this guideline. 2) Hypotension, hypothermia, and metabolic disturbances should be treated and corrected and medications that can interfere with the neurologic examination and apnea testing should be discontinued allowing for adequate clearance before proceeding with these evaluations. 3) Two examinations, including apnea testing with each examination separated by an observation period, are required. Examinations should be performed by different attending physicians. Apnea testing may be performed by the same physician. An observation period of 24 hrs for term newborns (37 wks gestational age) to 30 days of age and 12 hrs for infants and children (>30 days to 18 yrs) is recommended. The first examination determines the child has met the accepted neurologic examination criteria for brain death. The second examination confirms brain death based on an unchanged and irreversible condition. Assessment of neurologic function after cardiopulmonary resuscitation or other severe acute brain injuries should be deferred for ≥24 hrs if there are concerns or inconsistencies in the examination. 4) Apnea testing to support the diagnosis of brain death must be performed safely and requires documentation of an arterial Paco2 20 mm Hg above the baseline and ≥60 mm Hg with no respiratory effort during the testing period. If the apnea test cannot be safely completed, an ancillary study should be performed. 5) Ancillary studies (electroencephalogram and radionuclide cerebral blood flow) are not required to establish brain death and are not a substitute for the neurologic examination. Ancillary studies may be used to assist the clinician in making the diagnosis of brain death a) when components of the examination or apnea testing cannot be completed safely as a result of the underlying medical condition of the patient; b) if there is uncertainty about the results of the neurologic examination; c) if a medication effect may be present; or d) to reduce the interexamination observation period. When ancillary studies are used, a second clinical examination and apnea test should be performed and components that can be completed must remain consistent with brain death. In this instance, the observation interval may be shortened and the second neurologic examination and apnea test (or all components that are able to be completed safely) can be performed at any time thereafter. 6) Death is declared when these criteria are fulfilled.