Neuroprotective strategies of cerebrolysin for the treatment of infants with neonatal hypoxic-ischemic encephalopathy.

BACKGROUND: Perinatal asphyxia (PA) is a devastating neonatal condition characterized by a lack of oxygen supporting the organ systems. PA can lead to hypoxic-ischemic encephalopathy (HIE), a brain dysfunction due to oxygen deprivation with a complex neurological sequela. The pathophysiology of HIE and PA is not entirely understood, with therapeutic hypothermia being the standard treatment with only limited value. However, alternative neuroprotective therapies can be a potential treatment modality. METHODS: In this review, we will characterize the biochemical mechanisms of PA and HIE, while also giving insight into cerebrolysin, a neuroprotective treatment used for HIE and PA. RESULTS: We found that cerebrolysin has up to 6-month treatment window post-ischemic insult. Cerebrolysin injections of 0.1 ml/kg of body weight twice per week were found to provide gross motor and speech deficit improvement. CONCLUSION: Our literature search emphasizes the positive effects of cerebrolysin for general improvement outcomes. Nevertheless, biomarker establishment is warranted to improve patient outcomes.

Sustained Inflation During Chest Compression: A New Technique of Pediatric Cardiopulmonary Resuscitation That Improves Recovery and Survival in a Pediatric Porcine Model.

Background Chest compression (CC) during sustained inflations (CC+SI) compared with CC with asynchronized ventilation (CCaV) during cardiopulmonary resuscitation in asphyxiated pediatric piglets will reduce time to return of spontaneous circulation (ROSC). Methods and Results Piglets (20-23 days of age, weighing 6.2-10.2 kg) were anesthetized, intubated, instrumented, and exposed to asphyxia. Cardiac arrest was defined as mean arterial blood pressure <25 mm Hg with bradycardia. After cardiac arrest, piglets were randomized to CC+SI (n=12) or CCaV (n=12) or sham (n=8). Sham-operated animals had no asphyxia. Heart rate, arterial blood pressure, carotid blood flow, cerebral oxygenation, and respiratory parameters were continuously recorded. There were no differences in baseline parameters or the duration and degree of asphyxiation. Median (interquartile range) Time to ROSC was 248 (41-346) seconds compared with 720 (167-720) seconds in the CC+SI group and CCaV group, respectively (P=0.0292). There was a 100% higher rate of ROSC in the CC+SI group versus CCaV group, with 10 (83%) versus 5 (42%) achieving ROSC (P=0.089), respectively. Piglets in the CC+SI and CCaV groups received intravenous epinephrine boluses to achieve ROSC (8/12 versus 10/12 P=0.639). There was a significantly higher minute ventilation in the CC+SI group, which was secondary to a 5-fold increase in the number of inflations per minute and a 1.5-fold increase in tidal volume. Conclusions CC+SI reduced time to ROSC and improved survival compared with using CCaV. CC+SI allowed passive ventilation of the lung while providing chest compressions. This technique warrants further studies to examine the potential to improve outcomes in pediatric patients with cardiac arrest. Registration URL: https://www.preclinicaltrials.eu; Unique identifier: PCTE0000152.

Neurovascular coupling (NVC) in newborns using processed EEG versus amplitude-EEG.

There is a critical need for development of real time physiological biomarkers for birth asphyxia that constitutes a major global public health burden. Our recent study (Scientific Reports, V10:9183, 2020) established a novel non-invasive neurovascular coupling (NVC) assessment in newborns using dynamic wavelet transform coherence (WTC) analysis irrespective of different aEEG algorithms. As an extended study, the current paper examines whether the variability in processed EEG and amplitude-EEG (aEEG) outputs would impact the determination of NVC in newborns with encephalopathy. Concurrent processed EEG tracings and regional near infrared spectroscopy (NIRS)-based cerebral tissue oxygen saturation (SctO2) readings during a period of twenty hours in their first day of life were selected and processed in this study. After bandpass-filtered in 2-15 Hz, rectified, and down-sampled at 0.21 Hz, the processed EEG tracings along with NIRS-SctO2 (0.21 Hz) were used to perform WTC analysis, followed by comparison of WTC-metrics between SctO2-processed EEG coherence and SctO2-aEEG coherence using Bland-Altman statistics. Our results demonstrated high and significant correlation (R2 = 0.96, p < 0.001) between NVC assessments by SctO2-processed EEG and SctO2-aEEG coherence, confirming that band-passed, rectified, and down-sampled processed EEG, or aEEG, can be paired with NIRS-SctO2 to assess NVC in newborns with encephalopathy. Findings indicate the feasibility of a simpler approach to NVC in neonates by using directly processed EEG, instead of aEEG.

Effect of therapeutic hypothermia on renal and myocardial function in asphyxiated (near) term neonates: A systematic review and meta-analysis.

BACKGROUND: Therapeutic hypothermia (TH) is a well-established neuroprotective therapy applied in (near) term asphyxiated infants. However, little is known regarding the effects of TH on renal and/or myocardial function. OBJECTIVES: To describe the short- and long-term effects of TH on renal and myocardial function in asphyxiated (near) term neonates. METHODS: An electronic search strategy incorporating MeSH terms and keywords was performed in October 2019 and updated in June 2020 using PubMed and Cochrane databases. Inclusion criteria consisted of a RCT or observational cohort design, intervention with TH in a setting of perinatal asphyxia and available long-term results on renal and myocardial function. We performed a meta-analysis and heterogeneity and sensitivity analyses using a random effects model. Subgroup analysis was performed on the method of cooling. RESULTS: Of the 107 studies identified on renal function, 9 were included. None of the studies investigated the effects of TH on long-term renal function after perinatal asphyxia. The nine included studies described the effect of TH on the incidence of acute kidney injury (AKI) after perinatal asphyxia. Meta-analysis showed a significant difference between the incidence of AKI in neonates treated with TH compared to the control group (RR = 0.81; 95% CI 0.67-0.98; p = 0.03). No studies were found investigating the long-term effects of TH on myocardial function after neonatal asphyxia. Possible short-term beneficial effects were presented in 4 out of 5 identified studies, as observed by significant reductions in cardiac biomarkers and less findings of myocardial dysfunction on ECG and cardiac ultrasound. CONCLUSIONS: TH in asphyxiated neonates reduces the incidence of AKI, an important risk factor for chronic kidney damage, and thus is potentially renoprotective. No studies were found on the long-term effects of TH on myocardial function. Short-term outcome studies suggest a cardioprotective effect.

Effects of varying chest compression depths on carotid blood flow and blood pressure in asphyxiated piglets.

BACKGROUND: Current neonatal resuscitation guidelines recommend chest compressions (CCs) should be delivered to a depth of approximately 1/3 of the anterior-posterior (AP) chest diameter. The aim of the study was to investigate the haemodynamic effects of different CC depths in a neonatal piglet model. METHODS: CCs were performed with an automated CC machine with 33%, 40% and 25% AP chest diameter in all piglets in the same order for a duration of 3 min each. RESULTS: Eight newborn piglets (age 1-3 days, weight 1.7-2.3 kg) were included in the study. Carotid blood flow (CBF) and systolic blood pressure were the highest using a CC depth of 40% AP chest diameter (19.3±7.5 mL/min/kg and 58±32 mm Hg). CONCLUSION: CC depth influences haemodynamic parameters in asphyxiated newborn piglets during cardiopulmonary resuscitation. The highest CBF and systolic blood pressure were achieved using a CC depth of 40% AP chest diameter. TRIAL REGISTRATION NUMBER: PCTE0000148.

Continuous chest compressions with asynchronous ventilations increase carotid blood flow in the perinatal asphyxiated lamb model.

BACKGROUND: The neonatal resuscitation program (NRP) recommends interrupted chest compressions (CCs) with ventilation in the severely bradycardic neonate. The conventional 3:1 compression-to-ventilation (C:V) resuscitation provides 90 CCs/min, significantly lower than the intrinsic newborn heart rate (120-160 beats/min). Continuous CC with asynchronous ventilation (CCCaV) may improve the success of return of spontaneous circulation (ROSC). METHODS: Twenty-two near-term fetal lambs were randomized to interrupted 3:1 C:V (90 CCs + 30 breaths/min) or CCCaV (120 CCs + 30 breaths/min). Asphyxiation was induced by cord occlusion. After 5 min of asystole, resuscitation began following NRP guidelines. The first dose of epinephrine was given at 6 min. Invasive arterial blood pressure and left carotid blood flow were continuously measured. Serial arterial blood gases were collected. RESULTS: Baseline characteristics between groups were similar. Rate of and time to ROSC was similar between groups. CCCaV was associated with a higher PaO2 (partial oxygen tension) (22 ± 5.3 vs. 15 ± 3.5 mmHg, p < 0.01), greater left carotid blood flow (7.5 ± 3.1 vs. 4.3 ± 2.6 mL/kg/min, p < 0.01) and oxygen delivery (0.40 ± 0.15 vs. 0.13 ± 0.07 mL O2/kg/min, p < 0.01) compared to 3:1 C:V. CONCLUSIONS: In a perinatal asphyxiated cardiac arrest lamb model, CCCaV showed greater carotid blood flow and cerebral oxygen delivery compared to 3:1 C:V resuscitation. IMPACT: In a perinatal asphyxiated cardiac arrest lamb model, CCCaV improved carotid blood flow and oxygen delivery to the brain compared to the conventional 3:1 C:V resuscitation. Pre-clinical studies assessing neurodevelopmental outcomes and tissue injury comparing continuous uninterrupted chest compressions to the current recommended 3:1 C:V during newborn resuscitation are warranted prior to clinical trials.

Neural Function Recovery and Safety of Mild Hypothermia Therapy Combined with Monosialotetrahexosylganglioside on Neonatal Asphyxia Complicated by Hypoxic Ischemic Encephalopathy.

OBJECTIVE: To explore the effect and safety of mild hypothermia therapy combined with monosialotetrahexosylganglioside (GM1) on neural function recovery of neonatal asphyxia complicated by hypoxic ischemic encephalopathy (HIE). METHODS: The clinical data of 90 neonates with HIE were retrospectively analyzed. According to the treatment methods, the neonates were divided into a routine group, a mild hypothermia group, and a combination group, with 30 cases in each group. The differences in neural function recovery, biochemical indexes, clinical signs recovery, efficacy, and complications were observed in the three groups after treatment. RESULTS: After treatment, the score of neonatal behavioral neurological assessment (NBNA) and level of superoxide dismutase (SOD) in the combination group were higher than those of the other two groups (P < 0.05). The levels of neuron-specific enolase (NSE), S-100ß protein, and plasma neuropeptide Y (NPY) in the combination group were lower than those in the other two groups, and the recovery time of consciousness, muscle tension, and reflex was shorter (P < 0.05). The combination group showed higher total effective rate and lower incidence of complications as compared with the other two groups (P < 0.05). CONCLUSION: Mild hypothermia therapy combined with GM1 for the treatment of neonatal asphyxia complicated by HIE can promote the recovery of neural function and reduce the incidence of complications in neonates.

Phenobarbital and midazolam suppress neonatal seizures in a noninvasive rat model of birth asphyxia, whereas bumetanide is ineffective.

OBJECTIVE: Neonatal seizures are the most frequent type of neurological emergency in newborn infants, often being a consequence of prolonged perinatal asphyxia. Phenobarbital is currently the most widely used antiseizure drug for treatment of neonatal seizures, but fails to stop them in ~50% of cases. In a neonatal hypoxia-only model based on 11-day-old (P11) rats, the NKCC1 inhibitor bumetanide was reported to potentiate the antiseizure activity of phenobarbital, whereas it was ineffective in a human trial in neonates. The aim of this study was to evaluate the effect of clinically relevant doses of bumetanide as add-on to phenobarbital on neonatal seizures in a noninvasive model of birth asphyxia in P11 rats, designed for better translation to the human term neonate. METHODS: Intermittent asphyxia was induced for 30 minutes by exposing the rat pups to three 7 + 3-minute cycles of 9% and 5% O2 at constant 20% CO2 . Drug treatments were administered intraperitoneally either before or immediately after asphyxia. RESULTS: All untreated rat pups had seizures within 10 minutes after termination of asphyxia. Phenobarbital significantly blocked seizures when applied before asphyxia at 30 mg/kg but not 15 mg/kg. Administration of phenobarbital after asphyxia was ineffective, whereas midazolam (0.3 or 1 mg/kg) exerted significant antiseizure effects when administered before or after asphyxia. In general, focal seizures were more resistant to treatment than generalized convulsive seizures. Bumetanide (0.3 mg/kg) alone or in combination with phenobarbital (15 or 30 mg/kg) exerted no significant effect on seizure occurrence. SIGNIFICANCE: The data demonstrate that bumetanide does not increase the efficacy of phenobarbital in a model of birth asphyxia, which is consistent with the negative data of the recent human trial. The translational data obtained with the novel rat model of birth asphyxia indicate that it is a useful tool to evaluate novel treatments for neonatal seizures.

Abnormalities in evoked potentials associated with abnormal glycemia and brain injury in neonatal hypoxic-ischemic encephalopathy.

OBJECTIVE: To investigate how functional integrity of ascending sensory pathways measured by visual and somatosensory evoked potentials (VEP & SEP) is associated with abnormal glycemia and brain injury in newborns treated with hypothermia for hypoxic-ischemic encephalopathy (HIE). METHODS: Fifty-four neonates ≥ 36 weeks gestational age with HIE underwent glucose testing, VEPs, SEPs, and magnetic resonance imaging (MRI) the first week of life. Minimum and maximum glucose values recorded prior to evoked potential (EP) testing were compared with VEP and SEP measures using generalized estimating equations. Relationships between VEP and SEP measures and brain injury on MRI were assessed. RESULTS: Maximum glucose is associated with decreased P200 amplitude, and increased odds that N300 peak will be delayed/absent. Minimum glucose is associated with decreased P22 amplitude. Presence of P200 and N300 peaks is associated with decreased odds of brain injury in the visual processing pathway, with delayed/absent N300 peak associated with increased odds of brain injury in posterior white matter. CONCLUSIONS: Deviations from normoglycemia are associated with abnormal EPs, and abnormal VEPs are associated with brain injury on MRI in cooled neonates with HIE. SIGNIFICANCE: Glucose is a modifiable risk factor associated with atypical brain function in neonates with HIE despite hypothermia treatment.

Excess cerebral oxygen delivery follows return of spontaneous circulation in near-term asphyxiated lambs.

Hypoxic-ischaemia renders the neonatal brain susceptible to early secondary injury from oxidative stress and impaired autoregulation. We aimed to describe cerebral oxygen kinetics and haemodynamics immediately following return of spontaneous circulation (ROSC) and evaluate non-invasive parameters to facilitate bedside monitoring. Near-term sheep fetuses [139 ± 2 (SD) days gestation, n = 16] were instrumented to measure carotid artery (CA) flow, pressure, right brachial arterial and jugular venous saturation (SaO2 and SvO2, respectively). Cerebral oxygenation (crSO2) was measured using near-infrared spectroscopy (NIRS). Following induction of severe asphyxia, lambs received cardiopulmonary resuscitation using 100% oxygen until ROSC, with oxygen subsequently weaned according to saturation nomograms as per current guidelines. We found that oxygen consumption did not rise following ROSC, but oxygen delivery was markedly elevated until 15 min after ROSC. CrSO2 and heart rate each correlated with oxygen delivery. SaO2 remained > 90% and was less useful for identifying trends in oxygen delivery. CrSO2 correlated inversely with cerebral fractional oxygen extraction. In conclusion, ROSC from perinatal asphyxia is characterised by excess oxygen delivery that is driven by rapid increases in cerebrovascular pressure, flow, and oxygen saturation, and may be monitored non-invasively. Further work to describe and limit injury mediated by oxygen toxicity following ROSC is warranted.

Effects of antenatal dexamethasone and hyperglycemia on cardiovascular adaptation to asphyxia in preterm fetal sheep.

Antenatal glucocorticoids improve outcomes among premature infants but are associated with hyperglycemia, which can exacerbate hypoxic-ischemic injury. It is still unclear how antenatal glucocorticoids or hyperglycemia modulate fetal cardiovascular adaptations to severe asphyxia. In this study, preterm fetal sheep received either saline or 12 mg im maternal dexamethasone, followed 4 h later by complete umbilical cord occlusion (UCO) for 25 min. An additional cohort of fetuses received titrated glucose infusions followed 4 h later by UCO to control for the possibility that hyperglycemia contributed to the cardiovascular effects of dexamethasone. Fetuses were studied for 7 days after UCO. Maternal dexamethasone was associated with fetal hyperglycemia (P < 0.001), increased arterial pressure (P < 0.001), and reduced femoral (P < 0.005) and carotid (P < 0.05) vascular conductance before UCO. UCO was associated with bradycardia, femoral vasoconstriction, and transient hypertension. For the first 5 min of UCO, fetal blood pressure in the dexamethasone-asphyxia group was greater than saline-asphyxia (P < 0.001). However, the relative increase in arterial pressure was not different from saline-asphyxia. Fetal heart rate and femoral vascular conductance fell to similar nadirs in both saline and dexamethasone-asphyxia groups. Dexamethasone did not affect the progressive decline in femoral vascular tone or arterial pressure during continuing UCO. By contrast, there were no effects of glucose infusions on the response to UCO. In summary, maternal dexamethasone but not fetal hyperglycemia increased fetal arterial pressure before and for the first 5 min of prolonged UCO but did not augment the cardiovascular adaptations to acute asphyxia.

A new index of ultrasonography for estimating cerebral circulation in newborn infants.

PURPOSE: To quantitatively estimate the influence of ductal shunt on cerebral blood flow and establish a new index of ultrasonography for estimating cerebral circulation without the influence of ductal shunt in newborn infants. METHODS: We retrospectively examined the records of anterior cerebral artery (ACA) and left pulmonary artery (LPA) blood flow velocity curves recorded by pulsed Doppler ultrasonography within 6 h after birth in 123 newborn infants without asphyxia (normal group) and in 31 newborn infants with asphyxia (asphyxia group). RESULTS: In the normal group, the resistance index (RI) of the ACA showed a positive correlation with the ratio of LPA diastolic-to-systolic flow velocities (LPAD/LPAS) (P < 0.001, r = 0.58), and the estimated RI (eRI) of the ACA was calculated using the following formula: Y = 0.47X + 0.67 (Y estimated RI; X LPAD/LPAS). In the asphyxia group, the RI of the ACA showed a weak correlation to base excess (BE) (P < 0.05, r = 0.46). The eRI of the ACA was calculated by the LPAD/PLAS in the asphyxia group, and the difference between the RI and eRI showed a better correlation to BE than RI (P < 0.001, r = 0.64). CONCLUSION: We determined the relation between cerebral blood flow RI and ductal shunt, and (RI - eRI) may be a new useful ultrasonographic index indicating cerebral circulation without the influence of ductal shunt in newborn infants.

Hypothermia and Cardiovascular Instability.

Severely asphyxiated neonates have acute heart failure as part of their multiorgan dysfunction syndrome during the first days of life. Supporting the cardiovascular system during this phase is part of contemporary treatment and regarded as vital for limiting the neurodevelopmental injury. The decision to treat cardiovascular instability should be based on evaluation of end-organ function. Neonatologist-performed echocardiography in combination with other diagnostic modalities enables comprehensive real-time assessment. This review discusses associations between hemodynamics and adverse outcome, modalities for evaluating the hemodynamic state of the infant, and therapeutic approaches during intensive care.

Rigor of Neurovascular Coupling (NVC) Assessment in Newborns Using Different Amplitude EEG Algorithms.

Birth asphyxia constitutes a major global public health burden for millions of infants with a critical need for real time physiological biomarkers. This proof of concept study targets the translational rigor of such biomarkers and aims to examine whether the variability in the amplitude-integrated EEG (aEEG) outputs impact the determination of neurovascular coupling (NVC) in newborns with encephalopathy. A convenience sample with neonatal asphyxia were monitored for twenty hours in the first day of life with EEG and near infrared spectroscopy (NIRS)-based cerebral tissue oxygen saturation (SctO2). NVC between aEEG and NIRS-SctO2 was assessed using wavelet transform coherence (WTC) analysis, specifically by the wavelet total pixel number of significant coherences within 95% confidence interval. The raw EEG was converted to aEEG using three different methods: Method (M1) derives from the algorithm by Zhang and Ding. Method (M2) uses a Neonatal EEG Analysis Toolbox (WU-NEAT). Method (M3) extracts output directly from a commercial platform with an undisclosed algorithm. Our results demonstrate excellent agreement with Bland Altman comparisons for WTC-based NVC irrespective of the algorithms used, despite significant heterogeneities in the aEEG tracings produced by three algorithms. Our findings confirm the robustness of NVC wavelet analysis in Neonatal Encephalopathy related to HIE.

Brain interstitial pH changes in the subacute phase of hypoxic-ischemic encephalopathy in newborn pigs.

Brain interstitial pH (pHbrain) alterations play an important role in the mechanisms of neuronal injury in neonatal hypoxic-ischemic encephalopathy (HIE) induced by perinatal asphyxia. The newborn pig is an established large animal model to study HIE, however, only limited information on pHbrain alterations is available in this species and it is restricted to experimental perinatal asphyxia (PA) and the immediate reventilation. Therefore, we sought to determine pHbrain over the first 24h of HIE development in piglets. Anaesthetized, ventilated newborn pigs (n = 16) were instrumented to control major physiological parameters. pHbrain was determined in the parietal cortex using a pH-selective microelectrode. PA was induced by ventilation with a gas mixture containing 6%O2-20%CO2 for 20 min, followed by reventilation with air for 24h, then the brains were processed for histopathology assessment. The core temperature was maintained unchanged during PA (38.4±0.1 vs 38.3±0.1°C, at baseline versus the end of PA, respectively; mean±SEM). In the arterial blood, PA resulted in severe hypoxia (PaO2: 65±4 vs 23±1*mmHg, *p<0.05) as well as acidosis (pHa: 7.53±0.03 vs 6.79±0.02*) that is consistent with the observed hypercapnia (PaCO2: 37±3 vs 160±6*mmHg) and lactacidemia (1.6±0.3 vs 10.3±0.7*mmol/L). Meanwhile, pHbrain decreased progressively from 7.21±0.03 to 5.94±0.11*. Reventilation restored pHa, blood gases and metabolites within 4 hours except for PaCO2 that remained slightly elevated. pHbrain returned to 7.0 in 29.4±5.5 min and then recovered to its baseline level without showing secondary alterations during the 24 h observation period. Neuropathological assessment also confirmed neuronal injury. In conclusion, in spite of the severe acidosis and alterations in blood gases during experimental PA, pHbrain recovered rapidly and notably, there was no post-asphyxia hypocapnia that is commonly observed in many HIE babies. Thus, the neuronal injury in our piglet model is not associated with abnormal pHbrain or low PaCO2 over the first 24 h after PA.

Hemodynamic Instability in Hypoxic Ischemic Encephalopathy: More Than Just Brain Injury-Understanding Physiology, Assessment, and Management.

Hypoxic-ischemic encephalopathy (HIE) can have both transient and long-lasting effects on the neonate, including neurologic, renal, cardiac, hepatic, and hematologic. Both the disease process and the treatment option of therapeutic hypothermia can result in hemodynamic instability. Understanding the effects of HIE on the neonatal myocardium, pulmonary vascular bed, and the cardiac dysfunction that can occur is key to managing infants with HIE. This article focuses on causes of hemodynamic instability in neonates following perinatal asphyxia and how to recognize hemodynamic compromise. It reviews the underlying pathophysiology and associated management strategies to improve hemodynamics and potentially improve outcomes.

Risk factors for neonatal seizures: A case-control study in the province of Parma, Italy.

PURPOSE: The present study evaluated the risk factors for electroencephalographic (EEG)-confirmed seizures during the whole neonatal period in preterm and term neonates born in the province of Parma between January 2009 and December 2014. METHODS: We selected as cases the infants that presented EEG-confirmed neonatal seizures (NS). Two population controls for each case were matched by gestational age (GA), sex, hospital, and period of birth. Information on the mother, the pregnancy, the labor and delivery, and the neonates were taken from the Emilia-Romagna Certificate of Delivery Assistance database and from hospital charts and ICD-9-CM codes. RESULTS AND INTERPRETATION: In the 6-year period of this study, 22 patients were recorded with NS. The association between at least one pregnancy complication and at least one neonatal complication, a low Apgar score, the need for resuscitation at birth, intraventricular hemorrhages (IVH) grades II-IV for preterm, and acute perinatal asphyxia/hypoxic-ischemic encephalopathy (HIE) for term infants were all statistically significant among cases. Neonates presenting these risk factors are more prone to develop NS and have to be strictly monitored.

Hypoxia - Reoxygenation in neonatal cardiac arrest: Results from experimental models.

In this review, we summarize the results of studies that investigated the effects of hypoxia and reoxygenation in cardiac arrest, including the use of different fractions of inspired oxygen, in neonatal animals. The studies were heterogenous in terms of anaesthetic regimens, and definitions of cardiac arrest and circulatory recovery. Cardiopulmonary resuscitation with 100% oxygen increased oxidative stress in maturing rats. Studies in fetal/neonatal lambs and post-transitional neonatal piglets indicate no consistent differences between ventilation with 21% vs. 100% oxygen with regards to recovery times, oxygen damage or adverse events. If 21% oxygen is as effective as 100% oxygen in newborn infants with cardiac arrest requiring chest compression, the use of 21% instead of 100% oxygen could reduce morbidity and mortality in asphyxiated infants. Unanswered questions include what is the most optimal cerebral oxygen delivery during reperfusion, as well as oxygenation targets after return of spontaneous circulation.

TLR7 agonist modulation of postasphyxial neurophysiological and cardiovascular adaptations in preterm fetal sheep.

Activation of Toll-like receptors (TLRs) after hypoxic-ischemic brain injury can exacerbate injury but also alleviate cell loss, as recently demonstrated with the TLR7 agonist Gardiquimod (GDQ). However, TLR agonists also modulate vascular function and neuronal excitability. Thus, we examined the effects of TLR7 activation with GDQ on cardiovascular function and seizures after asphyxia in preterm fetal sheep at 0.7 gestation (104 days, term ∼147 days). Fetuses received sham asphyxia or asphyxia induced by umbilical cord occlusion for 25 min or asphyxia followed by a continuous intracerebroventricular infusion of 3.34 mg of GDQ from 1 to 4 h after asphyxia. Fetuses were monitored continuously for 72 h postasphyxia. GDQ treatment was associated with sustained, moderate hypertension for 72 h (P < 0.05), with a transient increase in heart rate. Electroencephalographic (EEG) power was suppressed for the entire postasphyxial period in both groups, whereas EEG spectral edge transiently increased during the GDQ infusion compared with asphyxia alone (P < 0.05), with higher ß- and lower δ-EEG frequencies (P < 0.05). This increase in EEG frequency was not related to epileptiform activity. After the GDQ infusion, there was earlier onset of high-amplitude stereotypic evolving seizures, with increased numbers of seizures and seizure burden (P < 0.05). Hemodynamic function and seizure activity are important indices of preterm wellbeing. These data highlight the importance of physiological monitoring during preclinical testing of potential neuroprotective strategies.

Asynchronous ventilation at 120 compared with 90 or 100 compressions per minute improves haemodynamic recovery in asphyxiated newborn piglets.

OBJECTIVE: To determine whether different chest compression (CC) rates during continuous CC with asynchronous ventilations (CCaV) reduce time to return of spontaneous circulation (ROSC) and improved haemodynamic recovery in piglets aged 24-72 hours with asphyxia-induced asystole. METHODS: Thirty piglets (aged 24-72 hours) were anaesthetised, intubated, instrumented and exposed to 30 min normocapnic hypoxia followed by asphyxia. Piglets were randomised into four groups: CCaV with CC rate of 90 (CCaV+90, n=8), 100 (CCaV+100, n=8) or 120 compressions per minute (CCaV+120, n=8), and a sham-operated group (n=6). Cardiac function, carotid blood flow, cerebral and renal oxygenation and respiratory parameters were continuously recorded. Cerebral cortical tissue was harvested and assayed for inflammatory and injury markers. RESULTS: All three intervention groups had a similar number of piglets achieving ROSC (6/8, 5/8 and 5/8 for CCaV+120, CCaV+100 and CCaV+90, respectively) and mean ROSC time (120, 90 and 90 s for CCaV+120, CCaV+100 and CCaV+90, respectively). The haemodynamic recovery (indicated by carotid flow, cerebral and renal perfusion) was similar between CCaV+120 and sham by the end of experiment. In comparison, CCaV+90 and CCaV+100 had significantly reduced haemodynamic recovery compared with sham operated (p≤0.05). Inflammatory (interleukin [IL]-6 and IL-1ß) and injury markers (lactate) were significantly higher in the frontoparietal cortex of CCaV+90 and CCaV+100 compared with sham, whereas brain injury markers were similar between CCaV+120 and sham. CONCLUSIONS: Although there was no difference between the groups in achieving ROSC, the haemodynamic recovery of CCaV+120 was significantly improved compared with CCaV+90 and CCaV+100, which were also associated with higher cerebral inflammatory and brain injury markers.