Reducing Pediatric Unplanned Extubation Across Multiple ICUs Using Quality Improvement.

OBJECTIVES: Unplanned extubation (UE) in pediatric patients can result in significant harm or mortality. In our institution, efforts to reduce UE in the ICU were siloed and learnings were not shared. Our goal was to implement shared initiatives across ICUs in a pediatric institution using quality improvement methodology, with the global aim of reducing serious harm caused by UEs. METHODS: The study was conducted as a single-center prospective quality improvement initiative in the pediatric, neonatal, and cardiac ICUs of a large, freestanding academic pediatric hospital. Using the model for improvement and plan-do-study-act cycles, our multidisciplinary team implemented multiple interventions to reduce UEs. The primary measure monitored was the monthly UE rate, defined as the number of UEs per 100 ventilator days, which was tracked over time using statistical control charts. RESULTS: The overall monthly institutional UE rate was reduced from 1.22 UE per 100 ventilator days to 0.2 UE per 100 ventilator days, representing an 84% improvement in rate and reduction of harm. Sixteen percent to 21% of UEs required additional resources because of a difficult airway, and 10% to 22% of UEs resulted in cardiovascular collapse requiring resuscitation. CONCLUSIONS: Significant harm is associated with UEs in pediatric patients. We implemented a bundle for UE reduction across all ICU populations in a pediatric hospital and significantly reduced the rate of UE within our institution and within each individual unit. Allowing variation for implementation of interventions by unit, although targeting a common goal, contributed to overall success and sustainability.

The Generalizability of a Medication Administration Discrepancy Detection System: Quantitative Comparative Analysis.

BACKGROUND: As a result of the overwhelming proportion of medication errors occurring each year, there has been an increased focus on developing medication error prevention strategies. Recent advances in electronic health record (EHR) technologies allow institutions the opportunity to identify medication administration error events in real time through computerized algorithms. MED.Safe, a software package comprising medication discrepancy detection algorithms, was developed to meet this need by performing an automated comparison of medication orders to medication administration records (MARs). In order to demonstrate generalizability in other care settings, software such as this must be tested and validated in settings distinct from the development site. OBJECTIVE: The purpose of this study is to determine the portability and generalizability of the MED.Safe software at a second site by assessing the performance and fit of the algorithms through comparison of discrepancy rates and other metrics across institutions. METHODS: The MED.Safe software package was executed on medication use data from the implementation site to generate prescribing ratios and discrepancy rates. A retrospective analysis of medication prescribing and documentation patterns was then performed on the results and compared to those from the development site to determine the algorithmic performance and fit. Variance in performance from the development site was further explored and characterized. RESULTS: Compared to the development site, the implementation site had lower audit/order ratios and higher MAR/(order + audit) ratios. The discrepancy rates on the implementation site were consistently higher than those from the development site. Three drivers for the higher discrepancy rates were alternative clinical workflow using orders with dosing ranges; a data extract, transfer, and load issue causing modified order data to overwrite original order values in the EHRs; and delayed EHR documentation of verbal orders. Opportunities for improvement were identified and applied using a software update, which decreased false-positive discrepancies and improved overall fit. CONCLUSIONS: The execution of MED.Safe at a second site was feasible and effective in the detection of medication administration discrepancies. A comparison of medication ordering, administration, and discrepancy rates identified areas where MED.Safe could be improved through customization. One modification of MED.Safe through deployment of a software update improved the overall algorithmic fit at the implementation site. More flexible customizations to accommodate different clinical practice patterns could improve MED.Safe's fit at new sites.

Human-Based Errors Involving Smart Infusion Pumps: A Catalog of Error Types and Prevention Strategies.

Over 4000 preventable injuries due to medication errors occur each year in any given hospital. Smart pumps have been widely introduced as one means to prevent these errors. Although smart pumps have been implemented to prevent errors, they fail to prevent specific types of errors in the medication administration process and may introduce new errors themselves. As a result, unique prevention strategies have been implemented by providers. No catalog of smart pump error types and prevention strategies currently exists. The aim of this study is to review and catalog the types of human-based errors related to smart pump use identified in the literature and to summarize the associated error-prevention strategies. We searched MEDLINE, PubMed, PubMed Central, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) for literature pertaining to human-based errors associated with smart pumps. Studies related to smart pump implementation, other types of pumps, and mechanical failures were excluded. Final selections were mapped for error types and associated prevention strategies. A total of 1177 articles were initially identified, and 105 articles were included in the final review. Extraction of error types and prevention strategies resulted in the identification of 18 error types and ten prevention strategies. Through a comprehensive literature review, we compiled a catalog of smart pump-related errors and associated prevention strategies. Strategies were mapped to error types to provide an initial framework for others to use as a resource in their error reviews and improvement work. Future research should assess the application of the resources provided by this review.

Assessment of an Unplanned Extubation Bundle to Reduce Unplanned Extubations in Critically Ill Neonates, Infants, and Children.

Importance: Unplanned extubations (UEs) in children contribute to significant morbidity and mortality, with an arbitrary benchmark target of less than 1 UE per 100 ventilator days. However, there have been no multicenter initiatives to reduce these events. Objective: To determine if a multicenter quality improvement initiative targeting all intubated neonatal and pediatric patients is associated with a reduction in UEs and morbidity associated with UE events. Design, Setting, and Participants: This multicenter quality improvement initiative enrolled patients from pediatric, neonatal, and cardiac intensive care units (ICUs) in 43 participating children's hospitals from March 2016 to December 2018. All patients with an endotracheal tube requiring mechanical ventilation were included in the study. Interventions: Participating hospitals implemented a quality improvement bundle to reduce UEs, which included standardized anatomic reference points and securement methods, protocol for high-risk situations, and multidisciplinary apparent cause analyses. Main Outcomes and Measures: The main outcome measures for this study included bundle compliance with each factor tested and UE rates on the center level and on the cohort level. Results: Among the 43 children's hospitals, the quality improvement initiative was associated with an aggregate 24.1% reduction in UE events, from a baseline rate of 1.135 UEs per 100 ventilator days to 0.862 UEs per 100 ventilator days. Across ICU settings studied, the pediatric ICU and neonatal ICU demonstrated centerline shifts, with an absolute reduction in events of 20.6% (from a baseline rate of 0.729 UEs per 100 ventilator days to 0.579 UEs per 100 ventilator days) and 17.6% (from a baseline rate of 1.555 UEs per 100 ventilator days to 1.282 UEs per 100 ventilator days), respectively. Most UEs required reintubation within 1 hour (mean of 120 of 206 events per month [58.3%]), followed by UEs that did not require reintubation (mean of 78 of 206 events per month [37.9%]) and UEs that resulted in cardiovascular collapse (mean of 8 of 206 events per month [3.9%]). Cardiovascular collapse events represented the most significant consequence of UE studied, and the collaborative reduced these UE events by 36.6%, from a study baseline rate of 0.041 UEs per 100 ventilator days to 0.026 UEs per 100 ventilator days. Conclusions and Relevance: This multicenter quality improvement initiative was associated with a reduction in UEs across different pediatric populations in diverse settings. A significant reduction in event rate and rate of harm (cardiovascular collapse) was observed, which was sustained over the time course of the intervention. This quality improvement process and UE bundle may be considered standard of care for pediatric hospitals in the future.

Smart pumps improve medication safety but increase alert burden in neonatal care.

BACKGROUND: Smart pumps have been widely adopted but there is limited evidence to understand and support their use in pediatric populations. Our objective was to assess whether smart pumps are effective at reducing medication errors in the neonatal population and determine whether they are a source of alert burden and alert fatigue in an intensive care environment. METHODS: Using smart pump records, over 370,000 infusion starts for continuously infused medications used in neonates and infants hospitalized in a level IV NICU from 2014 to 2016 were evaluated. Attempts to exceed preset soft and hard maximum limits, percent variance from those limits, and pump alert frequency, patterns and salience were evaluated. RESULTS: Smart pumps prevented 160 attempts to exceed the hard maximum limit for doses that were as high as 7-29 times the maximum dose and resulted in the reprogramming or cancellation of 2093 infusions after soft maximum alerts. While the overall alert burden from smart pumps for continuous infusions was not high, alerts clustered around specific patients and medications, and a small portion (17%) of infusions generated the majority of alerts. Soft maximum alerts were often overridden (79%), consistent with low alert salience. CONCLUSIONS: Smart pumps have the ability to improve neonatal medication safety when compliance with dose error reducing software is high. Numerous attempts to administer high doses were intercepted by dosing alerts. Clustered alerts may generate a high alert burden and limit safety benefit by desensitizing providers to alerts. Future efforts should address ways to improve alert salience.

Data Challenges With Real-Time Safety Event Detection And Clinical Decision Support.

BACKGROUND: The continued digitization and maturation of health care information technology has made access to real-time data easier and feasible for more health care organizations. With this increased availability, the promise of using data to algorithmically detect health care-related events in real-time has become more of a reality. However, as more researchers and clinicians utilize real-time data delivery capabilities, it has become apparent that simply gaining access to the data is not a panacea, and some unique data challenges have emerged to the forefront in the process. OBJECTIVE: The aim of this viewpoint was to highlight some of the challenges that are germane to real-time processing of health care system-generated data and the accurate interpretation of the results. METHODS: Distinct challenges related to the use and processing of real-time data for safety event detection were compiled and reported by several informatics and clinical experts at a quaternary pediatric academic institution. The challenges were collated from the experiences of the researchers implementing real-time event detection on more than half a dozen distinct projects. The challenges have been presented in a challenge category-specific challenge-example format. RESULTS: In total, 8 major types of challenge categories were reported, with 13 specific challenges and 9 specific examples detailed to provide a context for the challenges. The examples reported are anchored to a specific project using medication order, medication administration record, and smart infusion pump data to detect discrepancies and errors between the 3 datasets. CONCLUSIONS: The use of real-time data to drive safety event detection and clinical decision support is extremely powerful, but it presents its own set of challenges that include data quality and technical complexity. These challenges must be recognized and accommodated for if the full promise of accurate, real-time safety event clinical decision support is to be realized.

Foxc2 is required for proper cardiac neural crest cell migration, outflow tract septation, and ventricle expansion.

BACKGROUND: Proper development of the great vessels of the heart and septation of the cardiac outflow tract requires cardiac neural crest cells. These cells give rise to the parasympathetic cardiac ganglia, the smooth muscle layer of the great vessels, some cardiomyocytes, and the conotruncal cushions and aorticopulmonary septum of the outflow tract. Ablation of cardiac neural crest cells results in defective patterning of each of these structures. Previous studies have shown that targeted deletion of the forkhead transcription factor C2 (Foxc2), results in cardiac phenotypes similar to that derived from cardiac neural crest cell ablation. RESULTS: We report that Foxc2-/- embryos on the 129s6/SvEv inbred genetic background display persistent truncus arteriosus and hypoplastic ventricles before embryonic lethality. Foxc2 loss-of-function resulted in perturbed cardiac neural crest cell migration and their reduced contribution to the outflow tract as evidenced by lineage tracing analyses together with perturbed expression of the neural crest cell markers Sox10 and Crabp1. Foxc2 loss-of-function also resulted in alterations in PlexinD1, Twist1, PECAM1, and Hand1/2 expression in association with vascular and ventricular defects. CONCLUSIONS: Our data indicate Foxc2 is required for proper migration of cardiac neural crest cells, septation of the outflow tract, and development of the ventricles. Developmental Dynamics 247:1286-1296, 2018. © 2018 Wiley Periodicals, Inc.

Designing and evaluating an automated system for real-time medication administration error detection in a neonatal intensive care unit.

Background: Timely identification of medication administration errors (MAEs) promises great benefits for mitigating medication errors and associated harm. Despite previous efforts utilizing computerized methods to monitor medication errors, sustaining effective and accurate detection of MAEs remains challenging. In this study, we developed a real-time MAE detection system and evaluated its performance prior to system integration into institutional workflows. Methods: Our prospective observational study included automated MAE detection of 10 high-risk medications and fluids for patients admitted to the neonatal intensive care unit at Cincinnati Children's Hospital Medical Center during a 4-month period. The automated system extracted real-time medication use information from the institutional electronic health records and identified MAEs using logic-based rules and natural language processing techniques. The MAE summary was delivered via a real-time messaging platform to promote reduction of patient exposure to potential harm. System performance was validated using a physician-generated gold standard of MAE events, and results were compared with those of current practice (incident reporting and trigger tools). Results: Physicians identified 116 MAEs from 10 104 medication administrations during the study period. Compared to current practice, the sensitivity with automated MAE detection was improved significantly from 4.3% to 85.3% (P = .009), with a positive predictive value of 78.0%. Furthermore, the system showed potential to reduce patient exposure to harm, from 256 min to 35 min (P < .001). Conclusions: The automated system demonstrated improved capacity for identifying MAEs while guarding against alert fatigue. It also showed promise for reducing patient exposure to potential harm following MAE events.

Using Health Information Technology to Improve Safety in Neonatal Care: A Systematic Review of the Literature.

Health information technology (HIT) interventions may improve neonatal patient safety but may also introduce new errors. The objective of this review was to evaluate the evidence for use of HIT interventions to improve safety in neonatal care. Evidence for improvement exists for interventions like computerized provider order entry in the neonatal population, but is lacking for several other interventions. Many unique applications of HIT are emerging as technology and use of the electronic health record expands. Future research should focus on the impact of these interventions in the neonatal population.

Endothelial cells are not required for specification of respiratory progenitors.

Crosstalk between mesenchymal and epithelial cells influences organogenesis in multiple tissues, such as lung, pancreas, liver, and the nervous system. Lung mesenchyme comprises multiple cell types, however, and precise identification of the mesenchymal cell type(s) that drives early events in lung development remains unknown. Endothelial cells have been shown to be required for some aspects of lung epithelial patterning, lung stem cell differentiation, and regeneration after injury. Furthermore, endothelial cells are involved in early liver and pancreas development. From these observations we hypothesized that endothelial cells might also be required for early specification of the respiratory field and subsequent lung bud initiation. We first blocked VEGF signaling in E8.5 cultured foreguts with small molecule VEGFR inhibitors and found that lung specification and bud formation were unaltered. However, when we examined E9.5 mouse embryos carrying a mutation in the VEGFR Flk-1, which do not develop endothelial cells, we found that respiratory progenitor specification was impeded. Because the E9.5 embryos were substantially smaller than control littermates, suggesting the possibility of developmental delay, we isolated and cultured foreguts from mutant and control embryos on E8.5, when no size differences were apparent. We found that both specification of the respiratory field and lung bud formation occurred in mutant and control explants. These observations were unaffected by the presence or absence of serum. We also observed that hepatic specification and initiation occurred in the absence of endothelial cells, and that expansion of the liver epithelium in culture did not differ between mutant and control explants. Consistent with previously published results, we also found that pancreatic buds were not maintained in cultured foreguts when endothelial cells were absent. Our observations support the conclusion that endothelial cells are not required for early specification of lung progenitors and bud initiation, and that the diminished lung specification seen in E9.5 Flk-/- embryos is likely due to developmental delay resulting from the insufficient delivery of oxygen, nutrients, and other factors in the absence of a vasculature.

Automated detection of medication administration errors in neonatal intensive care.

OBJECTIVE: To improve neonatal patient safety through automated detection of medication administration errors (MAEs) in high alert medications including narcotics, vasoactive medication, intravenous fluids, parenteral nutrition, and insulin using the electronic health record (EHR); to evaluate rates of MAEs in neonatal care; and to compare the performance of computerized algorithms to traditional incident reporting for error detection. METHODS: We developed novel computerized algorithms to identify MAEs within the EHR of all neonatal patients treated in a level four neonatal intensive care unit (NICU) in 2011 and 2012. We evaluated the rates and types of MAEs identified by the automated algorithms and compared their performance to incident reporting. Performance was evaluated by physician chart review. RESULTS: In the combined 2011 and 2012 NICU data sets, the automated algorithms identified MAEs at the following rates: fentanyl, 0.4% (4 errors/1005 fentanyl administration records); morphine, 0.3% (11/4009); dobutamine, 0 (0/10); and milrinone, 0.3% (5/1925). We found higher MAE rates for other vasoactive medications including: dopamine, 11.6% (5/43); epinephrine, 10.0% (289/2890); and vasopressin, 12.8% (54/421). Fluid administration error rates were similar: intravenous fluids, 3.2% (273/8567); parenteral nutrition, 3.2% (649/20124); and lipid administration, 1.3% (203/15227). We also found 13 insulin administration errors with a resulting rate of 2.9% (13/456). MAE rates were higher for medications that were adjusted frequently and fluids administered concurrently. The algorithms identified many previously unidentified errors, demonstrating significantly better sensitivity (82% vs. 5%) and precision (70% vs. 50%) than incident reporting for error recognition. CONCLUSIONS: Automated detection of medication administration errors through the EHR is feasible and performs better than currently used incident reporting systems. Automated algorithms may be useful for real-time error identification and mitigation.

Phenotyping for patient safety: algorithm development for electronic health record based automated adverse event and medical error detection in neonatal intensive care.

BACKGROUND: Although electronic health records (EHRs) have the potential to provide a foundation for quality and safety algorithms, few studies have measured their impact on automated adverse event (AE) and medical error (ME) detection within the neonatal intensive care unit (NICU) environment. OBJECTIVE: This paper presents two phenotyping AE and ME detection algorithms (ie, IV infiltrations, narcotic medication oversedation and dosing errors) and describes manual annotation of airway management and medication/fluid AEs from NICU EHRs. METHODS: From 753 NICU patient EHRs from 2011, we developed two automatic AE/ME detection algorithms, and manually annotated 11 classes of AEs in 3263 clinical notes. Performance of the automatic AE/ME detection algorithms was compared to trigger tool and voluntary incident reporting results. AEs in clinical notes were double annotated and consensus achieved under neonatologist supervision. Sensitivity, positive predictive value (PPV), and specificity are reported. RESULTS: Twelve severe IV infiltrates were detected. The algorithm identified one more infiltrate than the trigger tool and eight more than incident reporting. One narcotic oversedation was detected demonstrating 100% agreement with the trigger tool. Additionally, 17 narcotic medication MEs were detected, an increase of 16 cases over voluntary incident reporting. CONCLUSIONS: Automated AE/ME detection algorithms provide higher sensitivity and PPV than currently used trigger tools or voluntary incident-reporting systems, including identification of potential dosing and frequency errors that current methods are unequipped to detect.

Large ABCA3 and SFTPC deletions resulting in lung disease.

RATIONALE: Mutations in genes encoding proteins important in the function and metabolism of pulmonary surfactant are recognized causes of lung disease. Clinical genetic testing is available for these disorders, but children with phenotypes consistent with surfactant dysfunction and no identifiable mutations in the known causative genes have been reported. OBJECTIVES: To identify the mechanism(s) for lung disease in two children with the phenotype of surfactant dysfunction who had negative testing in clinical laboratories for gene mutations causing surfactant dysfunction. METHODS: Amplicons spanning multiple exons of candidate genes were generated by polymerase chain reaction and sequenced. MEASUREMENTS AND MAIN RESULTS: A 4,335-base deletion that included all of exon 12 of the gene encoding member A3 of the adenosine triphosphate-binding cassette transporter was identified in a full-term infant with respiratory failure. A 333-base deletion involving part of exon 4 and the adjacent intron of the gene encoding surfactant protein C was identified in a child with interstitial lung disease. CONCLUSIONS: Large deletions are a cause of surfactant dysfunction disorders and may need to be sought for specifically in children whose phenotypes suggest these syndromes but in whom clinical genetic testing is unrevealing.

Neonates with tongue-based airway obstruction: a systematic review.

OBJECTIVE: In this systematic review, the authors summarize the current evidence in the literature regarding diagnosis, treatment, and long-term outcomes in neonates with tongue-based airway obstruction (TBAO) and assess the level of evidence of included studies. DATA SOURCES: The terms Pierre Robin syndrome/sequence, micrognathia, retrognathia, and cleft palate were combined with airway obstruction, treatment, tongue-lip plication, and osteogenesis distraction to perform an Ovid literature search, yielding 341 references. The authors excluded references containing patients with isolated choanal/nasal obstruction, patients older than 12 months, and expert opinion papers, yielding 126 articles. REVIEW METHODS: The authors searched 3 electronic databases and reference lists of existing reviews from 1980 to October 2010 for articles pertaining to the diagnosis, treatment, and outcomes of TBAO. Reviewers assigned a level of evidence score based on Oxford's Centre for Evidence Based Medicine scoring system and recorded relevant information. RESULTS: Most studies were case studies and single-center findings. The lack of standardization of diagnostic and treatment protocols and the heterogeneity of cohorts both within and between studies precluded a meta-analysis. There was little evidence beyond expert opinion and single-center evaluation regarding diagnosis, treatment, and long-term outcomes of neonates with TBAO. CONCLUSIONS: The variability in the phenotype of the cohorts studied and the absence of standardized indications for intervention preclude deriving any definitive conclusions regarding diagnostic tools to evaluate this patient population, treatment choices, or long-term outcomes. A coordinated multicenter study with a standardized diagnostic and treatment algorithm is recommended to develop evidence for the diagnosis and treatment of neonates with TBAO.

A phenotype-driven ENU mutagenesis screen identifies novel alleles with functional roles in early mouse craniofacial development.

Proper craniofacial development begins during gastrulation and requires the coordinated integration of each germ layer tissue (ectoderm, mesoderm, and endoderm) and its derivatives in concert with the precise regulation of cell proliferation, migration, and differentiation. Neural crest cells, which are derived from ectoderm, are a migratory progenitor cell population that generates most of the cartilage, bone, and connective tissue of the head and face. Neural crest cell development is regulated by a combination of intrinsic cell autonomous signals acquired during their formation, balanced with extrinsic signals from tissues with which the neural crest cells interact during their migration and differentiation. Although craniofacial anomalies are typically attributed to defects in neural crest cell development, the cause may be intrinsic or extrinsic. Therefore, we performed a phenotype-driven ENU mutagenesis screen in mice with the aim of identifying novel alleles in an unbiased manner, that are critically required for early craniofacial development. Here we describe 10 new mutant lines, which exhibit phenotypes affecting frontonasal and pharyngeal arch patterning, neural and vascular development as well as sensory organ morphogenesis. Interestingly, our data imply that neural crest cells and endothelial cells may employ similar developmental programs and be interdependent during early embryogenesis, which collectively is critical for normal craniofacial morphogenesis. Furthermore our novel mutants that model human conditions such as exencephaly, craniorachischisis, DiGeorge, and Velocardiofacial sydnromes could be very useful in furthering our understanding of the complexities of specific human diseases.

Interfering with Wnt signalling alters the periodicity of the segmentation clock.

Somites are embryonic precursors of the ribs, vertebrae and certain dermis tissue. Somite formation is a periodic process regulated by a molecular clock which drives cyclic expression of a number of clock genes in the presomitic mesoderm. To date the mechanism regulating the period of clock gene oscillations is unknown. Here we show that chick homologues of the Wnt pathway genes that oscillate in mouse do not cycle across the chick presomitic mesoderm. Strikingly we find that modifying Wnt signalling changes the period of Notch driven oscillations in both mouse and chick but these oscillations continue. We propose that the Wnt pathway is a conserved mechanism that is involved in regulating the period of cyclic gene oscillations in the presomitic mesoderm.

Partial SP-B deficiency perturbs lung function and causes air space abnormalities.

Surfactant protein B (SP-B) is required for function of newborn and adult lung, and partial deficiency has been associated with susceptibility to lung injury. In the present study, transgenic mice were produced in which expression of SP-B in type II epithelial cells was conditionally regulated. Concentrations of SP-B were maintained at 60-70% of that normally present in control. Immunostaining for SP-B demonstrated cellular heterogeneity in expression of the protein. In subsets of type II cells in which SP-B staining was decreased, immunostaining for pro-SP-C was increased and lamellar body ultrastructure was disrupted, consistent with focal SP-B deficiency. Fluorescence-activated cell sorting analyses of freshly isolated type II cells identified a population of cells with low SP-B content and a smaller population with increased SP-B content, confirming nonuniform expression of the SP-B transgene. Focal air space enlargement, without cellular infiltration or inflammation, was observed. Pressure-volume curves indicated that maximal tidal volume was unchanged; however, hysteresis was modestly altered and residual volumes were significantly decreased in the SP-B-deficient mice. Chronic, nonuniform SP-B deficiency perturbed pulmonary function and caused air space enlargement.

Gene expression and regulation of hindbrain and spinal cord development.

The formation of the central nervous system is one of the most fascinating processes in biology. Motor coordination, sensory perception and memory all depend on the complex cell connections that form with extraordinary precision between distinct nerve cell types within the central nervous system. The development of the central nervous system and its intricate connections occurs in several steps. During the first step known as neural induction, the neural plate forms as a uniform sheet of neuronal progenitors. Neural induction is followed by neurulation, the process in which the two halves of the neural plate are transformed into a hollow tube. Neurulation is accompanied by regionalisation of the neural tube anterior-posteriorly into the brain and spinal cord and dorso-ventrally into neural crest cells and numerous classes of sensory and motor neurons. The proper development of the vertebrate central nervous system requires the precise, finely balanced control of cell specification and proliferation, which is achieved through the complex interplay of multiple signaling systems. Bone morphogenetic proteins (BMPs), retinoic acid (RA) fibroblast growth factors (FGFs), Wnt and Hedgehog proteins are a few key factors that interact to pattern the developing central nervous system. In this review, we detail our current knowledge of the roles of these signaling factors in the development of the vertebrate nervous system in terms of the mechanisms underlying the formation and specification of the hindbrain and spinal cord.