Du Sweetman

Cardiovascular dysfunction in infants with neonatal encephalopathy

Severe perinatal asphyxia with hypoxic ischaemic encephalopathy occurs in approximately 1–2/1000 live births and is an important cause of cerebral palsy and associated neurological disabilities in children. Multiorgan dysfunction commonly occurs as part of the asphyxial episode, with cardiovascular dysfunction occurring in up to a third of infants. This narrative paper attempts to review the literature on the importance of early recognition of cardiac dysfunction using echocardiography and biomarkers such as troponin and brain type natriuretic peptide. These tools may allow accurate assessment of cardiac dysfunction and guide therapy to improve outcome.

Biomarkers of acute kidney injury in neonatal encephalopathy

Acute kidney injury (AKI) is a common complication of neonatal encephalopathy (NE). The accurate diagnosis of neonatal AKI, irrespective of the cause, relies on suboptimal methods such as identification of rising serum creatinine, decreased urinary output and glomerular filtration rate. Studies of AKI biomarkers in adults and children have shown that biomarkers can improve the early diagnosis of AKI. Hypoxia–ischaemia is the proposed aetiological basis of AKI in both NE and cardiopulmonary bypass (CPB). However, there is a paucity of studies examining the role of AKI biomarkers specifically in NE. Urinary cystatin C (CysC), neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18, kidney injury molecule-1, liver-type fatty acid-binding protein, serum CysC and serum NGAL all show good ability to predict early AKI in a heterogeneous critically ill neonatal population including infants post-CPB. Moreover, serum and urinary NGAL and urinary CysC are early predictors of AKI secondary to NE. These findings are promising and open up the possibility of biomarkers playing a significant role in the early diagnosis and treatment of NE-related AKI. There is an urgent need to explore the role of AKI biomarkers in infants with NE as establishing the diagnosis of AKI earlier may allow more timely intervention with potential for improving long-term outcome.

Management of renal dysfunction following term perinatal hypoxia‐ischaemia

Acute kidney injury frequently develops following the term perinatal hypoxia‐ischaemia. Quantifying the degree of acute kidney injury is difficult, however, as the methods currently in use are suboptimal. Acute kidney injury management is largely supportive with little evidence basis for many interventions. This review discusses management strategies and novel biomarkers that may improve diagnosis and management of renal injury following perinatal hypoxia‐ischaemia.

Cardiac biomarkers in neonatal hypoxic ischaemia

Following a perinatal hypoxic–ischaemic insult, term infants commonly develop cardiovascular dysfunction. Troponin‐T, troponin‐I and brain natriuretic peptide are sensitive indicators of myocardial compromise. The long‐term effects of cardiovascular dysfunction on neurodevelopmental outcome following perinatal hypoxic ischaemia remain controversial. Follow‐up studies are warranted to ensure optimal cardiac function in adulthood.

Perinatal Asphyxia and Erythropoietin and VEGF: Serial Serum and Cerebrospinal Fluid Responses.

Background: Infants with neonatal encephalopathy (NE) of hypoxic-ischaemic origin are at risk of oxidative and ischaemia-reperfusion injury, which may induce abnormal inflammatory responses involving excessive cytokine production and release in serum and cerebrospinal fluid (CSF). Systemic inflammation is found in infants with NE, and we therefore were interested in cytokines associated with hypoxia, including vascular endothelial growth factor (VEGF) and erythropoietin (Epo). Objective: To investigate the relationship between Epo, VEGF levels, brain injury and outcome in a group of term infants exposed to perinatal asphyxia (PA) compared to controls. Methods: Serum and CSF biomarkers associated with hypoxia (VEGF, Epo) were serially measured using multiplex immunoassays over days 1-4 in term infants exposed to PA including infants with NE and controls. Results were compared to severity of encephalopathy, MR brain imaging and mortality. Results: Ninety-four infants had 247 serum samples collected (n = 12 controls, 82 exposed to PA with 34 CSF samples), and 4 infants died. Controls had significantly lower serum Epo levels on days 1 and 2 compared to those exposed to PA (p = 0.02). Grade II/III NE was significantly associated with elevated day 2 Epo and decreased day 1 VEGF (p < 0.05; day 2 Epo AUC = 0.74, cut-off 10.05 IU/ml). Elevated serum Epo was associated with severely abnormal MRI. Mortality was associated with elevated day 3 Epo and decreased day 1 VEGF. CSF levels were all after hypothermia and were not significantly associated with outcome. Conclusion: Serum Epo and VEGF may be markers of severity of hypoxia-ischaemia and brain injury as they are closely related to hypoxic exposure.

Renal Function and Novel Urinary Biomarkers In Infants with Neonatal Encephalopathy

Perinatal asphyxia is associated with multi‐organ injury including acute kidney injury (AKI). New urinary biomarkers may detect more subtle renal injury.

Serial cytokine alterations and abnormal neuroimaging in newborn infants with encephalopathy.

Inflammatory cytokines may play a role in the final common pathway in the pathogenesis of hypoxic‐ischaemic injury in experimental models. We aimed to profile the systemic pro‐and anti‐inflammatory response over the first week of life in term infants at risk of neonatal encephalopathy.

PS-157 Moderate To Severe Neonatal Encephalopathy Is Predicted By Rising Serum But Not Csf Biomarkers

Background Term infants with NE of hypoxic-ischaemic origin, have been exposed to generalised oxidative injury which may cause excessive cytokine production and release in serum and CSF. Cytokine levels may correlate with severity of brain injury and aid in outcome prediction. Objective To investigate the relationship between serum and CSF biomarkers and NE in a group of term infants exposed to perinatal hypoxia-ischaemia compared to controls. Design/Methods Levels of serum and CSF biomarkers [VEGF, IL-8, Epo, GM-CSF] were serially measured over day 1–11 in a group of term newborns with NE and controls (serum only). These values were compared to grade of encephalopathy defined by Sarnat score. Results Twelve control and 82 cases had serum samples collected (Grade 0 NE = 6, Grade I NE = 23, Grade II NE = 42, Grade III NE = 11). Thirty-nine infants underwent TH, 4 infants died. Controls had significantly lower serum Epo on day 1–2 compared with cases (p-values < 0.05). Grade II/III NE was significantly associated with elevated serum Epo (Day 2), IL-8 (Day 2 and 6–8) (p-values < 0.05) and with decreased VEGF (Day 1). Grade II/III NE was best predicted by Epo and IL-8 (Day 2) and VEGF (Day 1) (p-values < 0.05). CSF biomarker levels (n = 34 infants) were not significantly associated with abnormal NE grade. Conclusions Term infants exposed to perinatal hypoxia-ischaemia have elevated levels of serum biomarkers compared to controls. Abnormal NE grade is best predicted by day 2 serum Epo and IL-8 while CSF levels were not predictive of outcome. Serum biomarkers may have a role in long term outcome prediction following NE.

PS-108 Urinary Biomarkers May Help Predict Outcome In Neonatal Encephalopathy

Background Following a perinatal hypoxic-is chaemic insult, term infants are at risk of multi-organ injury including AKI. Infants with NE experience up-regulation of urinary cytokines which may reflect severity of brain injury. Objective To investigate the association between novel urinary biomarkers and outcome in a group of term infants with NE compared to controls. Methods Levels of urinary biomarkers [Albumin, B2M, Cystatin-C, EGF, NGAL, Osteopontin, Uromodulin] were serially measured over day 1–11 in a group of term newborns with NE and controls. These values were compared to grade of encephalopathy defined by Sarnat score. Results Ten control and 82 cases had urine samples collected (Grade 0 NE = 7, Grade I NE = 22, Grade II NE = 42, Grade III NE = 11). Thirty-nine infants underwent TH, 4 infants died. Control infants had significantly lower B2M on day 1, NGAL on day 1–2 and significantly higher urinary EGF on day 2–3 and Uromodulin on day 3, compared with cases (p-values Conclusion Infants with NE have elevated urinary biomarkers compared to controls. Abnormal grade of encephalopathy is best predicted by day 2 urinary Cystatin-C and day 3 NGAL. Urinary biomarkers may have a role in long term outcome prediction following NE.

1097 Activated Protein C Decreases Endotoxin-Induced Inflammatory Responses in Infants with Neonatal Encephalopathy

Introduction Infection and inflammation can be antecedents of neonatal encephaloapthy (NE) and increase the risk of neurological sequelae. Activated protein C (APC) has anticoagulant and anti-inflammatory effects and provides neuroprotection in ischemic brain and spinal cord injury. Aims To examine neutrophil and monocyte responses to Lipopolysaccharide (LPS) in infants with NE (n= 22) and also the effect of APC compared with healthy adult controls (n=15). Methods Whole blood was incubated with LPS +/-APC and TLR4, CD11b expression, and reactive oxygen intermediate (ROI) release from neutrophils and monocytes was examined by flow cytometry. Results Neutrophil and monocyte CD11b expression was significantly increased in response to LPS in adults controls (p<0.001) and NE infants (p<0.001). However infants with NE were LPS-hyporesponsive compared to adults control and APC did not reduce this effect. Neutrophil TLR4 expression was significantly increased in response to LPS in NE infants on D3 compared to adults (p<0.001) and has been reduced by APC (p=0.03). LPS induced monocyte TLR4 was only significantly increased in NE infants D7 (p<0.001). Neutrophil ROI was significantly increased in Adults (p<0.001) and NE infants on D3 (p=0.021) following LPS and this response were significantly reduced by APC. Conclusion Neutrophil activation and production of ROI may mediate tissue damage in NE infants. APC modified LPS responses in adults and NE infants on D3 of life. APC may reduce the inflammatory responses secondary to hypoxia and possibly benefit these patients at high risk of inflammatory multiorgan dysfunction.