Neonatal Anesthesia Research Articles

Neonatal anesthesia impairs synapsin 1 and synaptotagmin 1, two key regulators of synaptic vesicle docking and fusion.

Early exposure to anesthetics may interfere with synaptic development and lead to cognitive deficits. We previously demonstrated a decrease in vesicles docked at and within 100 nm from the presynaptic membrane in hippocampal nerve terminals of neonatal rats after anesthesia. Hence, we designed this study to assess the effects of neonatal anesthesia on synapsin 1 (Syn1) and synaptotagmin 1 (Syt1), two key regulators of vesicle docking and fusion. To test the link between changes in Syn1 and Syt1 and behavioral deficits observed after neonatal anesthesia, we also assessed retention memory and fear conditioning in adolescent rats after neonatal anesthesia. Pups received a combination of clinical anesthetics, then Syn1 and Syt1 mRNA and protein expression were determined at the peak (postnatal day 8, P8), part-way through (P12) and end of synaptogenesis (P24) in the CA1-subiculum by qPCR and western blotting. Anesthesia decreased Syn1 and Syt1 mRNA expression at P8 (P<0.01 and <0.001) and P12 (P=0.001 and 0.017), but not P24 (P=0.538 and 0.671), and impaired Syn1, p-Syn1, and Syt1 protein levels at P8 (P=0.038, 0.041, and 0.004, respectively), P12 (P<0.001, P=0.001, and P<0.0001), and P24 (P=0.025, 0.031, and 0.001). Anesthetic-challenged rats displayed deficient long-term retention memory (P=0.019) and hippocampus-dependent fear conditioning (P<0.001). These results suggest that anesthetics alter Syn1 and Syt1 during synapse assembly and maturation, raising the possibility that anesthetic interference with Syn1 and Syt1 could initiate changes in synaptic function that contribute to the cognitive deficits observed after neonatal anesthesia.

The Comparison of Laryngeal Mask Airway and Endotracheal Tube in General Anesthesia for Premature Neonates

The Comparison of Laryngeal Mask Airway and Endotracheal Tube in General Anesthesia for Premature Neonates

Anesthesia for Premature Infants and Micropremies

Advances in medicine has led to the increased survival of micropremies and premature infants. The anesthetic management for these patients has unique considerations and should only be provided by experts at specialized pediatric centers. Technical procedures and monitoring can be challenging due to their small size. Related to the physiology and immaturity of the airway, respiratory, cardiac and neurologic systems, there is an increased perioperative risk that may be related to hypoxemia and apnea and rapid desaturation, reversal of intracardiac shunts, and intraventricular hemorrhage. Immature renal and hepatic systems are related to decreased drug metabolism and demand careful and accurate administration of medications. The patients are prone to hypothermia and hypoglycemia. In addition, there may be congenital anomalies, syndromes, or other metabolic issues that may not have been fully worked up at the time of presentation for anesthesia. Emerging information related to potential neurotoxicity related to exposure to anesthetic agents has led to continual research and understanding of these mechanisms in order to provide the safest care. A meticulous approach, careful planning, and collaborative approach with the multidisciplinary neonatal team are essential to ensure the best possible outcome for this unique patient population. This review contains 3 figures, 4 tables, and 36 references. Keywords: inguinal hernia repair, micropremies, prematurity, neonatal anesthesia, neurotoxicity, neonatal intensive care, necrotizing enterocolitis, preterm infants

Neonatal general anesthesia causes lasting alterations in excitatory and inhibitory synaptic transmission in the ventrobasal thalamus of adolescent female rats

Ample evidence has surfaced documenting the neurotoxic effects of various general anesthetic (GA) agents in the mammalian brain when administered at critical periods of synaptogenesis. However, little is known about how this neurotoxic insult affects persisting neuronal excitability after the initial exposure. Here we investigated synaptic activity and intrinsic excitability of the ventrobasal nucleus (VB) of the thalamus caused by neonatal GA administration. We used patch-clamp recordings from acute thalamic slices in young rats up to two weeks after neurotoxic GA exposure of isoflurane and nitrous oxide for 6 h at postnatal age of 7 (P7) days. We found that GA exposure at P7 increases evoked excitatory postsynaptic currents (eEPSCs) two fold by means through AMPA mediated mechanisms, while NMDA component was spared. In addition, miniature EPSCs showed a faster decay rate in neurons from GA treated animals when compared to sham controls. Likewise, we discovered that the amplitudes of evoked inhibitory postsynaptic currents (eIPSCs) were increased in VB neurons from GA animals about two-fold. Interestingly, these results were observed in female but not male rats. In contrast, intrinsic excitability and properties of T-type voltage gated calcium currents were minimally affected by GA exposure. Together, these data further the idea that GAs cause lasting alterations in synaptic transmission and neuronal excitability depending upon the placing and connectivity of neurons in the thalamus. Given that function of thalamocortical circuits critically depends on the delicate balance between excitation and inhibition, future development of therapies aimed at addressing consequences of altered excitability in the developing brain by GAs may be an attractive possibility.

Essentials of Anesthesia for Infants and Neonates

Essentials of Anesthesia for Infants and Neonates

Recent trends in paediatric regional anaesthesia

Paediatric regional anaesthesia today is one of the fastest growing and exciting aspects of paediatric anaesthesia, which requires an ongoing fervour to learn. Application of paediatric regional anaesthesia in neonates, infants, toddlers and children is undertaken to treat perioperative pain without disturbing the physiological milieu with additional advantages elaborated in the review. The available choices, traditional methods and the most recently described methods are discussed with emphasis on their advantages and disadvantages. Clear pointers for selection of the blocks are also discussed. To present a holistic overview of this rapidly growing subject, a comprehensive literature search was performed in May 2019 in MEDLINE, PubMed and Google Scholar to retrieve articles pertaining to all the above topics. The keywords used in various combinations included 'Central neuraxial, blocks, Paediatric(s)', 'Peripheral Nerve blocks', 'Safety, controversies, regional, anaesthesia'.

Anaesthetic concerns in preterm and term neonates.

Anaesthesia for neonates is a composite of good knowledge of neonatal and transitional physiology combined with skill in airway maintenance and vascular access. When the newborn is a preterm, the complexities of management increase due to the small size and accompanying issues such as bronchopulmonary dysplasia and apnoea. World over, the number of survivors of preterm birth is on the increase. We searched Pubmed for “Anesthesia, apnea, neonatal, neonates, physiology, preterm, spinal anesthesia”, as well as cross references from review articles. These babies have a high incidence of conditions warranting surgery (e.g., tracheoesophaeal fistula, congenital diaphragmatic hernia, anorectal malformations, incarcerated hernia, necrotising enterocolitis). The possibility of neurodevelopmental harm by anaesthetics is currently the topic of active research. In parallel, advances in paediatric anaesthesia equipment, use of regional and neuraxial anaesthesia and availability of monitoring have steadily increased the safety of anaesthesia in these tiny patients.

Use of remifentanil in general anesthesia for neonatal non-cardiac surgery: a case series

ObjectiveThis case series aimed to summarize our experience in usage of remifentanil in neonates undergoing non-cardiac surgery.BackgroundPhysiology of neonates and infants is different from that of adults. Immaturity of their vital organ systems narrows a safety margin of perioperative management including anesthesia. Remifentanil has favorable characteristics for pediatrics such as short duration of action and rapid elimination. Although remifentanil was introduced into clinical practice since 1996, its application to neonatal anesthesia has not been validated yet.MethodsThis is a 14-month retrospective case series of neonates receiving remifentanil during non-cardiac surgery at a tertiary care pediatric hospital in Japan. Patients’ characteristics, intraoperative data, and complications were retrieved from medical records.ResultsA total of 68 neonates underwent non-cardiac surgery under general anesthesia, of whom 48 received remifentanil. Infusion rate was 0.14 (0.04–0.35) mcg/kg/min (median, range). No intractable adverse events including postoperative apnea were detected.ConclusionRemifentanil is generally feasible to neonatal surgical population.

Essentials of Anesthesia for Infants and Neonates

Essentials of Anesthesia for Infants and Neonates

Sevoflurane anesthesia represses neurogenesis of hippocampus neural stem cells via regulating microRNA-183-mediated NR4A2 in newborn rats.

Sevoflurane has been commonly utilized in nonobstetric surgeries in pregnant women, and its impacts on fetal brain are still not completely known. Ectopic NR4A2 expression has been reported to be related with familial Parkinson disease, and through dual luciferase we found that NR4A2 is a target gene of microRNA-183 (miR-183). We proposed a hypothesis that miR-183 may participate in the process by targeting NR4A2 in neurons after sevoflurane anesthesia. To verify the effect of sevoflurane on hippocampal neural stem cells (NSCs) proliferation and differentiation, we conducted EdU assay and immunofluorescence staining. Next, for better understanding of the impact of miR-183, we altered the miR-183 expression using mimic and inhibitor. Meanwhile, the targeting relationship between miR-183 and NR4A2 was validated by a bioinformatics website and dual-luciferase reporter gene assay. Finally, expressions of miR-184, NR4A2, SRY (sex-determining region Y)-box 2 (Sox2), and brain-derived neurotrophic factor (BDNF) were determined and evaluated by reverse transcription quantitative polymerase chain reaction and western blot analysis. First, sevoflurane was determined a crucial factor in biological behaviors of hippocampal NSCs. Moreover, upregulated miR-183 expression by mimic inhibited the proliferation and differentiation of NSCs. Sevoflurane negatively regulated NR4A2 and Sox2 expressions but positively regulated miR-183 and BDNF expressions. Our findings revealed the underlying novel mechanism by which sevoflurane inhibits hippocampal NSC proliferation and differentiation through interaction with miR-183 and NR4A2. The study provides reliable reference for safe application of sevoflurane anesthesia in neonates.

Care of infants with gastroschisis in low-resource settings

There is great global disparity in the outcome of infants born with gastroschisis. Mortality approaches 100% in many low income countries. Barriers to better outcomes include lack of antenatal diagnosis, deficient pre-hospital care, ineffective neonatal resuscitation and venous access, limited intensive care facilities, poor access to the operating theatre and safe neonatal anesthesia, and lack of neonatal parenteral nutrition. However, lessons can be learned from the evolution in management of gastroschisis in high-income countries, generic efforts to improve neonatal survival in low- and middle-income countries as well as specific gastroschisis management initiatives in low-resource settings. Micro and meso-level interventions include educational outreach programs, and pre and in hospital management protocols that focus on resuscitation and include the delay or avoidance of early neonatal anesthesia by using a preformed silo or equivalent. Furthermore, multidisciplinary team training, nurse empowerment, and the intentional involvement of mothers in monitoring and care provision may contribute to improving survival. Macro level interventions include the incorporation of ultrasound into World Health Organisation antenatal care guidelines to improve antenatal detection and the establishment of the infrastructure to enable parenteral nutrition provision for neonates in low- and middle-income countries. On a global level, gastroschisis has been suggested as a bellwether condition for evaluating access to and outcomes of neonatal surgical care provision.

Neonatal exposure to sevoflurane caused cognitive deficits by dysregulating SK2 channels and GluA2-lacking AMPA receptors in juvenile rat hippocampus

Anesthetics exposure to neonates leads to impairment of hippocampal synaptic plasticity and cognitive functions later in life. This phenomenon complies with the concept of metaplasticity: a priming stimulation can affect induction of synaptic plasticity mins or days later. We aimed to understand whether small conductance Ca2+-activated potassium channel type2 (SK2) and subunit composition of AMPA receptors are altered and contribute to sevoflurane-induced metaplasticity. To fulfill this goal, we exposed neonatal rats (postnatal day 7) to 2% sevoflurane for 2 h (sevoflurane rats) and examined synaptic plasticity in the hippocampus and cognitive function in juvenile rats (postnatal day 30–35). We observed that the juvenile sevoflurane rats showed elevation in the threshold for LTP induction, facilitation of LTD induction, and cognitive dysfunctions. Meanwhile, these rats also exhibited increased surface expression of SK2 and enhanced synaptic recruitment of GluA2-lacking AMPA receptors, which possess stronger inward rectification. Blocking SK2 eliminated inward rectification of AMPA receptors in juvenile sevoflurane rats. Interestingly, blocking either SK2 channels or GluA2-lacking AMPA receptors normalized LTP, LTD, and spatial memory in juvenile sevoflurane rats. Our data indicate that neonatal sevoflurane anesthesia have negative impact on cognitive function extended to juvenile rats probably through increasing surface expression of SK2 and synaptic recruitment of GluA2-lacking AMPA receptors. This study provides a new sight for sevoflurane induced metaplasticity.

Effects of combined brief etomidate anesthesia and postnatal stress on amygdala expression of Cl− cotransporters and corticotropin-releasing hormone and alcohol intake in adult rats

Early life stressors, including general anesthesia, can have adverse effects on adult neural and behavioral outcomes, such as disruptions in inhibitory signaling, stress responsivity and increased risk of psychiatric disorders. Here we used a rat model to determine the effects of combined exposure to etomidate (ET) neonatal anesthesia and maternal separation on adult amygdala expression of genes for corticotropin-releasing hormone (Crh) and the chloride co-transporters Nkcc1 and Kcc2, as well as ethanol intake. Male and female Sprague-Dawley rats were subjected to 2 h of ET anesthesia on postnatal days (P) 4, 5, or 6 followed by maternal separation for 3 h on P10 (ET + SEP). During the P91-P120 period rats had daily 2 h access to three 0.05% saccharin solutions containing 0%, 5%, or 10% ethanol, followed by gene expression analyses. The ET + SEP group had increased Crh mRNA levels and Nkcc1/Kcc2 mRNA ratios in the amygdala, with greater increases in Nkcc1/Kcc2 mRNA ratios in males. A moderate increase in 5% ethanol intake was evident in the ET + SEP males, but not females, after calculation of the ratio of alcohol intake between the last week and first week of exposure. In contrast, control males tended to decrease alcohol consumption during the same period. A brief exposure to ET combined with a subsequent episode of stress early in life induced significant alterations in expression of amygdala Crh, Nkcc1 and Kcc2 with greater changes in the Cl− transporter expression in males. The possibility of increased alcohol intake in the exposed males requires further confirmation using different alcohol intake paradigms.

Nasal cannula technique for ventilating during the administration of general anesthesia in neonates and pediatric patients

ABSTRACTObjective: Minor surgeries on the oral cavity, e.g., frenulectomies, are often performed under general mask anesthesia. The objective is to present the nasal cannula technique for ventilating step-by-step method for ventilating during general anesthesia for minor surgeries in neonates and pediatric patients.Technique: The nasal cannula technique for ventilating has been used in over 20 pediatric cases (neonates and toddlers), without the need to re-mask during the procedure and without complications or oxygen desaturations. After induction of general mask anesthesia, propofol with or without adjunctive ketamine is administered. The anesthesia mask is exchanged with a nasal cannula, using the largest sized prongs that accommodate the nares, and the nasal cannula is connected to the anesthesia circuit. This permits administration of inspired fractions of oxygen.Conclusion: The nasal cannula technique for ventilating provides a safe method for delivering general anesthesia and ventilating during minor surgeries for neonates and pediatric patients.

Safe anesthesia for neonates, infants and children.

This review provides an overview of the perioperative safety concerns in pediatric anesthesia and exploration of strategies to minimize these risks through education and training in pediatric anesthesia. There is increasing human data on the effects of general anesthesia for surgery and procedures on later neurodevelopment. However, the magnitude and relevance of this remains unclear while the long-term outcomes from recent human studies are awaited. The current known and established risks associated with pediatric anesthesia can be minimized by establishing a robust and safe conduct of anesthesia. This not only includes maintenance of normal physiological variables but also other aspects such as reduction of preoperative fear and anxiety and postoperative care. This can be achieved through effective multidisciplinary team working, cross specialty training and further development of fellowships and secondments.

Neonatal anesthesia exposure impacts brain microRNAs and their associated neurodevelopmental processes

MicroRNAs (miRNAs), when subjected to environmental stimuli, can exhibit differential expression. As critical regulators of gene expression, differential miRNA expression has been implicated in numerous disorders of the nervous system. In this study, we focused on the effect of a general anesthetic, as an environmental stimulus, on miRNA expression of the developing brain. General anesthetics have potential long-lasting neurotoxic effects on the developing brain, resulting in behavioral changes in adulthood. We first carried out an unbiased profiling approach to examine the effect of single-episode neonatal general anesthetic, sevoflurance (sevo), exposure on miRNA expression of the brain. Neonatal sevo has a significant effect on the expression of specific miRNAs of the whole brain and the hippocampus that is both immediate – directly after neonatal treatment, as well as long-lasting - during adulthood. Functionally, neonatal sevo-associated miRNA gene-targets share potential neurodevelopmental pathways related to axon guidance, DNA transcription, protein phosphorylation and nervous system development. Our understanding on the role of miRNAs provides a putative epigenetic/molecular bridge that links neonatal general anesthetic’s effect with its associated functional change.

Noninvasive Tracking of Anesthesia Neurotoxicity in the Developing Rodent Brain.

Potential deleterious effect of multiple anesthesia exposures on the developing brain remains a clinical concern. We hypothesized that multiple neonatal anesthesia exposures are more detrimental to brain maturation than an equivalent single exposure, with more pronounced long-term behavioral consequences. We designed a translational approach using proton magnetic resonance spectroscopy in rodents, noninvasively tracking the neuronal marker N-acetyl-aspartate, in addition to tracking behavioral outcomes. Trajectories of N-acetyl-aspartate in anesthesia naïve rats (n = 62, postnatal day 5 to 35) were determined using proton magnetic resonance spectroscopy, creating an "N-acetyl-aspartate growth chart." This chart was used to compare the effects of a single 6-h sevoflurane exposure (postnatal day 7) to three 2-h exposures (postnatal days 5, 7, 10). Long-term effects on behavior were separately examined utilizing novel object recognition, open field testing, and Barnes maze tasks. Utilizing the N-acetyl-aspartate growth chart, deviations from the normal trajectory were documented in both single and multiple exposure groups, with z-scores (mean ± SD) of -0.80 ± 0.58 (P = 0.003) and -1.87 ± 0.58 (P = 0.002), respectively. Behavioral testing revealed that, in comparison with unexposed and single-exposed, multiple-exposed animals spent the least time with the novel object in novel object recognition (F(2,44) = 4.65, P = 0.015), traveled the least distance in open field testing (F(2,57) = 4.44, P = 0.016), but exhibited no learning deficits in the Barnes maze. Our data demonstrate the feasibility of using the biomarker N-acetyl-aspartate, measured noninvasively using proton magnetic resonance spectroscopy, for longitudinally monitoring anesthesia-induced neurotoxicity. These results also indicate that the neonatal rodent brain is more vulnerable to multiple anesthesia exposures than to a single exposure of the same cumulative duration.

The prevention of general anesthetic-induced development neurotoxicity

Background A number of studies have shown that anesthetics can cause the developing brain to degenerate. Objective This review provides references for neonatal and infant anesthesia. Content Review the current prevention measures of the general anesthetic induced developmental neurotoxicity. Trend With the adjustment of fertility policy, a growing number of pediatrics are using anesthetics for general anesthesia or sedation. In order to effectively avoid the general anesthesia-induced development neurotoxicity, we should understand measures to prevent neurotoxicity. Key words: Anesthetics; Drug toxicity; Central neural system

Consideraciones anestésicas en neonato polimalformado, para el cierre de mielomeningocele y colostomia, en mismo acto quirúrgico

La anestesia del neonato, por las características fisiológicas y la dificultad en la monitorización, puede resultar un reto. Además aquellos que requiere una cirugía mayor pueden asociar patologías que elevan la morbilidad del acto quirúrgico. El uso de monitorización no invasiva es relevante en este tipo de pacientes. Presentamos caso de neonato polimalformado al que se realiza anestesia general para citoscopia, corrección de mielomeningocele y colostomía.

Is spinal anaesthesia in young infants really safer and better than general anaesthesia?

Concerns regarding the potential neurotoxic effects of general anaesthesia have seen resurgence in awake spinal anaesthesia in neonates and infants. This review includes recently published data from a large prospective randomized controlled trial with view to determining if spinal anaesthesia is safer and better than general anaesthesia in this population. Compared with general anaesthesia, spinal anaesthesia results in less haemodynamic instability and fewer early (<30 min) apnoeic episodes in neonates and infants undergoing inguinal herniorraphy; the overall incidence of apnoeas in the first 12 h postoperatively was similar. Neurodevelopmental outcome 2 years postoperatively was similar. An appreciable failure rate for spinal anaesthesia was confirmed. Spinal anaesthesia represents a suitable alternative to general anaesthesia in neonates and infants undergoing minor surgery avoiding the need for endotracheal intubation and ventilation. Spinal anaesthesia has some advantages but a significant failure rat and has not been demonstrated to improve neurodevelopmental outcome.