Screening tools to evaluate the neurotoxic potential of botanicals: building a strategy to assess safety.

AREAS COVERED: This paper outlines the selection of NAMs, including in vitro assays using primary rat cortical neurons, zebrafish embryos, and Caenorhabditis elegans. These assays aim to assess neurotoxic endpoints such as neuronal activity and behavioral responses. Microelectrode array recordings of rat cortical neurons provide insights into the impact of botanical extracts on neuronal function, while the zebrafish embryos and C. elegans assays evaluate neurobehavioral responses. The paper also provides an account of the selection of botanical case studies based on expert judgment and existing neuroactivity/toxicity information. The proposed battery of assays will be tested with these case studies to evaluate their utility for neurotoxicity screening. EXPERT OPINION: The complexity of botanicals necessitates the use of multiple NAMs for effective neurotoxicity screening. This paper discusses the evaluation of methodologies to develop a robust framework for evaluating botanical safety, including complex neuronal models and key neurodevelopmental process assays. It aims to establish a comprehensive screening framework.

Balanced on the Biggest Wave: Nirsevimab for Newborns.

Respiratory syncytial virus (RSV) is the leading cause of hospitalization in infancy in the United States. Nearly all infants are infected by 2 years of age, with bronchiolitis requiring hospitalization often occurring in previously healthy children and long-term consequences of severe disease including delayed speech development and asthma. Incomplete passage of maternal immunity and a high degree of genetic variability within the virus contribute to morbidity and have also prevented successful neonatal vaccine development. Monoclonal antibodies reduce the risk of hospitalization from severe RSV disease, with palivizumab protecting high-risk newborns with comorbidities including chronic lung disease and congenital heart disease. Unfortunately, palivizumab is costly and requires monthly administration of up to five doses during the RSV season for optimal protection.Rapid advances in the past two decades have facilitated the identification of antibodies with broad neutralizing activity and allowed manipulation of their genetic code to extend half-life. These advances have culminated with nirsevimab, a monoclonal antibody targeting the Ø antigenic site on the RSV prefusion protein and protecting infants from severe disease for an entire 5-month season with a single dose. Four landmark randomized controlled trials, the first published in July 2020, have documented the efficacy and safety of nirsevimab in healthy late-preterm and term infants, healthy preterm infants, and high-risk preterm infants and those with congenital heart disease. Nirsevimab reduces the risk of RSV disease requiring medical attention (number needed to treat [NNT] 14-24) and hospitalization (NNT 33-63) with rare mild rash and injection site reactions. Consequently, the Centers for Disease Control and Prevention has recently recommended nirsevimab for all infants younger than 8 months of age entering or born during the RSV season and high-risk infants 8-19 months of age entering their second season. Implementing this novel therapy in this large population will require close multidisciplinary collaboration. Equitable distribution through minimizing barriers and maximizing uptake must be prioritized.

Successful Use of Intravenous Methylnaltrexone for Opioid-Induced Constipation in Critically Ill Pediatric Patients.

Objectives Methylnaltrexone is U.S. Food and Drug Administration (FDA) approved as a subcutaneous injection for adults with opioid-induced constipation (OIC). Case series have described the use of methylnaltrexone for OIC in the pediatric oncology population. There are limited data describing its intravenous use in critically ill pediatric patients. Methods We conducted a retrospective observational study at St. Louis Children's Hospital. Patients less than 18 years old who received at least one dose of intravenous methylnaltrexone while admitted to an intensive care unit between January 2016 and August 2019 were included. The primary outcome was documented laxation within 24 hours of methylnaltrexone administration. Results Sixteen patients received a total of 34 doses of intravenous methylnaltrexone. Patients received a median of 1.69 (interquartile range [IQR], 0.9-4.86) morphine milligram equivalents per kilogram per 24 hours, over a median of 14 days (IQR, 11-30), before methylnaltrexone administration. The median dose of methylnaltrexone was 0.15 mg/kg (IQR, 0.15-0.16). Ten patients (63%) responded to the first dose of methylnaltrexone, and 14 patients (88%) responded to at least one dose. Overall, 26 doses (76%) led to patient response. Four patients (25%) experienced adverse events (emesis, abdominal pain) after methylnaltrexone administration. No signs or symptoms of opioid withdrawal were documented. Conclusions Intravenous methylnaltrexone appears to be safe and effective in treating OIC in critically ill pediatric patients. No serious adverse events or signs of opioid withdrawal were observed after single and repeat dosing. Patients responded to methylnaltrexone with varying opioid dosing and durations prior to administration.

Dexmedetomidine During Therapeutic Hypothermia: A Multicenter Quality Initiative.

OBJECTIVES: Sedation is typically used during neonatal therapeutic hypothermia (TH). This report describes a quality improvement (QI) initiative with the aim of decreasing opioid exposure during TH by implementing dexmedetomidine as the primary sedative agent. METHODS: This dual-center QI initiative used a multidisciplinary team to create a sedation algorithm for safe implementation of dexmedetomidine as first-line therapy during TH. The primary measure in this initiative was cumulative opioid exposure during TH; balancing measures included safety parameters, primarily the rate of dexmedetomidine discontinuation because of bradycardia. Baseline demographic and clinical data were collected retrospectively for the period before implementation and prospectively during the QI period. Data were analyzed using statistical process control charts to identify change over time. RESULTS: One-hundred and fifty-four neonates in the 2-year pre-QI period were compared with 135 neonates in the 2 years after guideline implementation. Guideline compliance with dexmedetomidine initiation was 99% and compliance with initial dosing increased from 70% to 91% during the QI period. The cumulative dose of opioid during TH decreased by >90% by the end of the QI period. Dexmedetomidine was discontinued for transient bradycardia in 9.6% of the study population. No other adverse effects were observed. CONCLUSIONS: Dexmedetomidine may be used as the primary sedative during neonatal TH with a low incidence of adverse effects. Clinical trials evaluating the impact of sedation during TH on neurologic outcomes are needed.

Bad Liver and a Broken Heart: Hepatitis B in the Newborn.

Hepatitis B viral infection is a significant source of morbidity and mortality worldwide. The United States has experienced a precipitous drop in acute hepatitis B infection after the introduction and widespread adoption of recombinant vaccines. Neonates experience significant risk from both vertical and horizontal hepatitis B exposure during a period of immaturity of the innate and adaptive immune systems. Acquisition of hepatitis B virus at or near birth confers the highest lifetime risk of chronic infection and subsequent complications including liver cirrhosis and hepatocellular carcinoma. Pregnant women should be screened for the presence of hepatitis B surface antigen, indicating acute or chronic infection, and, if positive, hepatitis B viral deoxyribonucleic acid, allowing for quantification of viral load. The development of highly effective and safe recombinant vaccines allows partial protection of late preterm and term neonates immediately after birth. Additionally, administration of hepatitis B immune globulin in the setting of suspected or confirmed exposure supplements the immune response and decreases the risk of chronic infection. The optimal timing of vaccination is later in low-birth-weight neonates due to the aforementioned immune system immaturity. Health care providers serving neonates must familiarize themselves with national guidelines regarding hepatitis B vaccination and hepatitis B immune globulin therapy. Understanding the risks of infection and the evidence basis supporting vaccination and immunotherapy will allow providers to educate families and support decision-making, with the potential to eradicate this vaccine-preventable illness in our lifetime.

Gabapentin as Adjunctive Therapy in Neonatal Opioid Withdrawal Syndrome: A Case Series.

OBJECTIVE: We describe a single center experience with gabapentin as adjunctive therapy in infants with neonatal opioid withdrawal syndrome (NOWS). METHODS: We performed a retrospective chart review of infants receiving gabapentin for NOWS. Data points collected included patient's sex, gestational age, maternal opioid exposure, NOWS medication dosing and length of therapy, number of failed wean attempts, time to successful morphine wean and duration of morphine wean, length of stay in the neonatal intensive care unit (NICU), and NOWS medications at discharge. RESULTS: Six infants received gabapentin as adjunctive treatment for NOWS. All infants failed 2-4 morphine weans before initiation of gabapentin despite the addition of clonidine. All infants that received gabapentin were successfully weaned off morphine. The time to wean off morphine after gabapentin initiation varied from 4-35 days. Maximum gabapentin doses ranged from 15 - 42.7 mg/kg/day. Five infants were discharged from the NICU on gabapentin. CONCLUSIONS: Gabapentin appeared to facilitate successful morphine weans in six patients with NOWS who were previously unable to wean despite the initiation of clonidine.

Up in Smoke: The Impacts of Marijuana During Pregnancy.

Numerous drugs ingested during pregnancy can impact the developing fetus. Although some effects are apparent at birth as overt teratogenicity or profound neonatal withdrawal, others become apparent only after a careful long-term follow-up into childhood. Shifting legal and cultural attitudes toward marijuana have led to increased use during pregnancy. This shift should prompt health care providers to carefully consider the drug's mechanism of action, its interaction with the placenta, and the potential consequences of fetal exposure. The primary psychoactive compound in marijuana is Δ9-tetrahydrocannabinol (THC), which agonizes endogenous cannabinoid receptors. Cannabinoid receptors are present in the fetal brain early in gestation and appear to have an important role in the developing central nervous system. THC crosses the placenta in sufficient quantities to raise concerns about exogenous exposure during fetal development. Robust follow-up studies suggest that marijuana use during pregnancy contributes to suboptimal fetal growth. At school age, heavy prenatal marijuana exposure predicts challenges in executive function (specifically, memory and reasoning) and externalizing behavior (e.g., hyperactivity and inattention). Memory and behavioral problems persist into early adulthood. These challenges coincide with a higher risk of heavy marijuana use in offspring. In concert with a suboptimal environment, young adults may experience a higher risk of global cognitive impairment and/or delinquency. Importantly, these adverse outcomes appear to be mitigated by postnatal factors including home environment. Ongoing studies in the modern era will be vital to enhance our understanding of the mechanisms by which THC impacts the fetus and confirm or refute knowledge regarding long-term impact. This knowledge will inform both health care providers and parents in collaborative decision-making to optimize the outcome of children.

A Charter to Fundamentally Change the Role of Oral Corticosteroids in the Management of Asthma.

Asthma affects 339 million people worldwide, with an estimated 5-10% experiencing severe asthma. In emergency settings, oral corticosteroids (OCS) can be lifesaving, but acute and long-term treatment can produce clinically important adverse outcomes and increase the risk of mortality. Therefore, global guidelines recommend limiting the use of OCS. Despite the risks, research indicates that 40-60% of people with severe asthma are receiving or have received long-term OCS treatment. Although often perceived as a low-cost option, long-term OCS use can result in significant health impairments and costs owing to adverse outcomes and increased utilization of healthcare resources. Alternative treatment methods, such as biologics, may produce cost-saving benefits with a better safety profile. A comprehensive and concerted effort is necessary to tackle the continued reliance on OCS. Accordingly, a threshold for OCS use should be established to help identify patients at risk of OCS-related adverse outcomes. Receiving a total dose of more than 500 mg per year should trigger a review and specialist referral. Changes to national and local policies, following examples from other chronic diseases, will be crucial to achieving this goal. Globally, multiple barriers to change still exist, but specific steps have been identified to help clinicians reduce reliance on OCS. Implementing these changes will result in positive health outcomes for patients and social and economic benefits for societies.

Assessment and Management of Delirium in the Pediatric Intensive Care Unit: A Review.

Many critically ill patients suffer from delirium which is associated with significant morbidity and mortality. There is a paucity of data about the incidence, symptoms, or treatment of delirium in the pediatric intensive care unit (PICU). Risk factors for delirium are common in the PICU including central nervous system immaturity, developmental delay, mechanical ventilation, and use of anticholinergic agents, corticosteroids, vasopressors, opioids, or benzodiazepines. Hypoactive delirium is the most common subtype in pediatric patients; however, hyperactive delirium has also been reported. Various screening tools are validated in the pediatric population, with the Cornell Assessment of Pediatric Delirium (CAPD) applicable to the largest age range and able to detect signs and symptoms consistent with both hypo- and hyperactive delirium. Treatment of delirium should always include identification and reversal of the underlying etiology, reserving pharmacologic management for those patients without symptom resolution, or with significant impact to medical care. Atypical antipsychotics (olanzapine, quetiapine, and risperidone) should be used first-line in patients requiring pharmacologic treatment owing to their apparent efficacy and low incidence of reported adverse effects. The choice of atypical antipsychotic should be based on adverse effect profile, available dosage forms, and consideration of medication interactions. Intravenous haloperidol may be a potential treatment option in patients unable to tolerate oral medications and with significant symptoms. However, given the high incidence of serious adverse effects with intravenous haloperidol, routine use should be avoided. Dexmedetomidine should be used when sedation is needed and when clinically appropriate, given the positive impact on delirium. Additional well-designed trials assessing screening and treatment of PICU delirium are needed.

Eyesight to the Blind-Pharmacotherapy for Retinopathy of Prematurity.

Retinopathy of prematurity (ROP) places preterm infants at significant risk for blindness. Angiogenesis of retinal blood vessels relies on vascular endothelial growth factor (VEGF) released in response to physiologic in utero hypoxia. Relative hyperoxia and disruption in the supply of growth factors after preterm birth lead to cessation of normal vascular growth. Recovery of VEGF production after 32 weeks' postmenstrual age results in aberrant vascular growth, including the formation of fibrous scars with the potential to detach the retina. Ablation of aberrant vessels by mechanical or pharmacologic methods relies on timely diagnosis in the early stages of ROP. Mydriatic medications dilate the pupil to allow examination of the retina. Mydriasis is typically accomplished using a combination of topical phenylephrine, a potent alpha-receptor agonist, and cyclopentolate, an anticholinergic. Systemic absorption of these agents results in a high incidence of cardiovascular, gastrointestinal, and respiratory adverse effects. Procedural analgesia should include the topical anesthetic proparacaine, oral sucrose, and nonpharmacologic interventions like non-nutritive sucking. Analgesia is often incomplete, leading to investigation of systemic agents like oral acetaminophen. If ROP threatens retinal detachment, laser photocoagulation is utilized to arrest vascular growth. More recently, the VEGF-antagonists, bevacizumab and ranibizumab, have emerged as treatment options. Systemic absorption of intraocular bevacizumab and the profound consequences of diffuse disruption of VEGF in the setting of rapid, neonatal organogenesis require dose optimization and careful evaluation of long-term outcomes in clinical trials. Intraocular ranibizumab is likely a safer alternative; however, outstanding questions remain regarding efficacy. Optimal patient outcomes rely on a combination of risk management throughout neonatal intensive care, timely diagnosis through careful ophthalmologic examinations, and treatment when indicated with laser therapy and/or anti-VEGF intravitreal injection.

High Content Imaging and Quantification of Microglia Phagocytosis In Vitro.

Microglia function as the tissue-specific resident macrophages of the nervous system, performing immune and non-immune functions. These functions are critical to development and to maintain homeostasis in the nervous system throughout the lifespan, and during brain injury or disease. One method by which microglia maintain homeostasis is phagocytosis of aberrant proteins, extracellular debris, synapses, or apoptotic cells. Phagocytic function can be changed by environmental or genetic risk factors that affect microglia. These protocols present a rapid and simple in vitro high-content imaging protocol for studying phagocytosis in the murine microglia BV-2 cell line. High-content imaging and analysis enable versatility of the assay, which can be used to test multiple experimental conditions, or as a screening tool. © 2023 Wiley Periodicals LLC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA. Basic Protocol 1: Phagocytosis of fluorescently labeled particles Basic Protocol 2: Examining modifications to phagocytosis by test substances Basic Protocol 3: High content imaging and analysis of phagocytic cells.

Assessment of compatibility of rhIGF-1/rhIGFBP-3 with neonatal intravenous medications.

BACKGROUND: Recombinant human (rh)IGF-1/IGFBP-3 protein complex, administered as a continuous intravenous infusion in preterm infants, is being studied for the prevention of complications of prematurity. METHODS: We conducted in vitro studies to evaluate the physical and chemical compatibility of rhIGF-1/IGFBP-3 with medications routinely administered to preterm neonates. In vitro mixing of rhIGF-1/IGFBP-3 drug product with small-molecule test medications plus corresponding controls was performed. Physical compatibility was defined as no color change, precipitation, turbidity, gas evolution, no clinically relevant change in pH/osmolality or loss in medication content. Chemical compatibility of small molecules was assessed using liquid chromatography (e.g., reverse-phase HPLC and ion chromatography), with incompatibility defined as loss of concentration of ≥ 10%. A risk evaluation was conducted for each medication based on in vitro compatibility data and potential for chemical modification. RESULTS: In vitro physical compatibility was established for 11/19 medications: caffeine citrate, fentanyl, fluconazole, gentamicin, insulin, intravenous fat emulsion, midazolam, morphine sulfate, custom-mixed parenteral nutrition solution (with/without electrolytes), parenteral nutrition solution + intravenous fat emulsion, and vancomycin (dosed from a 5 mg/mL solution), but not for 8/19 medications: amikacin, ampicillin, dopamine, dobutamine, furosemide, meropenem, norepinephrine, and penicillin G, largely owing to changes in pH after mixing. Small-molecule compatibility was unaffected post-mixing, with no loss of small-molecule content. For physically compatible medications, risk analyses confirmed low probability and severity of a risk event. CONCLUSION: Co-administration of rhIGF-1/rhIGFBP-3 drug product with various medications was assessed by in vitro studies using case-by-case risk analyses to determine the suitability of the products for co-administration.

Variation in ampicillin dosing for lower respiratory tract infections and neonatal bacterial infections in US children's hospitals.

Objective: We examined ampicillin dosing in pediatric patients across 3 conditions: (1) bacterial lower respiratory tract infections (LRTIs) in infants and children >3 months, (2) neonates with suspected or proven sepsis, and (3) neonates with suspected central nervous system (CNS) infections. We compared our findings to dosing guidance for these specific indications. Design: Retrospective cohort study. Setting: The study included data from 32 children's hospitals in the United States. Methods: We reviewed prescriptions from the SHARPS study of antimicrobials, a survey of antibiotic prescribing from July 2016 to December 2017. Prescriptions were analyzed for indication, total daily dose per kilogram, and presence of antimicrobial stewardship program (ASP) review. LRTI prescriptions were compared to IDSA recommendations for community-acquired pneumonia. Neonatal prescriptions were compared to recommendations from the American Academy of Pediatrics (AAP). Prescriptions were categorized as "optimal" (80%-120% of recommended dosing), "suboptimal" (<80% of recommended dosing), or "excessive" (>120% of recommended dosing). Results: Among 1,038 ampicillin prescriptions, we analyzed 88 prescriptions for LRTI, 499 prescriptions for neonatal sepsis, and 27 prescriptions for neonatal CNS infection. Of the LRTI prescriptions, 77.3%were optimal. Of prescriptions for neonatal sepsis, 81.6% were excessive compared to AAP bacteremia recommendations but 78.8% were suboptimal compared to AAP meningitis guidelines. Also, 48.1% of prescriptions for neonatal CNS infection were suboptimal, and 50.6% of prescriptions were not reviewed by the ASP. Conclusions: LRTI dosing is generally within the IDSA-recommended range. However, dosing for neonatal sepsis often exceeds the recommendation for bacteremia but is below the recommendation for meningitis. This variability points to an important opportunity for future antimicrobial stewardship efforts.

No Code-The Role of Sodium Bicarbonate and Naloxone in Neonatal Resuscitation.

Resuscitations in neonates and infants present caregivers with challenging decisions in a highly stressful environment. Consideration of the pathophysiology of cardiac arrest and respiratory failure prior to an emergency allows for thoughtful utilization of pharmacotherapy. It is vital to remember that establishment of an airway and delivery of breaths and chest compressions should be prioritized. Epinephrine is first-line pharmacotherapy for severe bradycardia or cardiac arrest unresponsive to the provision of respiratory support and chest compressions. Sodium bicarbonate may be considered based on the intrinsic links between cardiac arrest, respiratory failure, and mixed acidosis. However, experimental and clinical data suggest that sodium bicarbonate worsens myocardial performance by several mechanisms (decreased intramyocardial pH, reduced oxygen delivery to tissues, reduced coronary perfusion pressure). Additionally, rapid administration of this hyperosmolar therapy may contribute to intracranial hemorrhage. With no clear benefit and multiple risks, sodium bicarbonate has been excluded from neonatal resuscitation algorithms. Opioids may produce respiratory depression in neonates, whether given to the mother prior to delivery or in neonatal intensive care; therefore, naloxone may be considered to restore respiratory drive. However, 50 years of neonatal utilization has not produced clinical studies documenting efficacy and safety. On the contrary, clinical studies fail to detect clear benefit and numerous concerning adverse reactions have been reported, including acute withdrawal, cardiorespiratory decompensation, and death. For these reasons, naloxone has also been removed from neonatal resuscitation algorithms. Clear understanding of pathophysiology, pharmacology, and clinical data support the use of multiple pharmacotherapies in neonatal resuscitation, including epinephrine, normal saline, intravenous glucose, adenosine, and calcium gluconate as reviewed in a previous column. The same pathways inform confident exclusion of sodium bicarbonate and naloxone.

Fentanyl Exposure in Preterm Infants: Five-Year Neurodevelopmental and Socioemotional Assessment.

Objective: To evaluate the association between cumulative fentanyl dose during neonatal intensive care and 5-year neurodevelopmental and socioemotional outcomes in very preterm infants. Materials and Methods: Patient demographics and clinical factors during the perinatal and neonatal course were collected in 84 patients born between 23- and 30-weeks gestational age (GA). Cumulative fentanyl dose during neonatal intensive care was calculated. Developmental testing at age 5 years included the Wechsler Preschool and Primary Scale of Intelligence Full-Scale Intelligence Quotient, Third Edition, Clinical Evaluation of Language Fundamentals-Preschool, Second Edition, Movement Assessment Battery for Children, Second Edition (MABC-2), and Shape School Assessment. Socioemotional outcomes were assessed via caregiver's responses on the Child Behavior Checklist/1.5-5 (CBCL/1.5-5.5) and Social Responsiveness Scale, Second Edition (SRS-2). Covariates were identified on bivariate analysis (p < 0.1). Linear regression models related outcome measures to the log of cumulative fentanyl dose adjusted for covariates. Results: Higher cumulative fentanyl dose was associated with lower composite motor scores on bivariate analysis (p < 0.01). Cumulative fentanyl dose did not correlate with composite intelligence quotient, language, or executive function. The Clinical Risk Index for Babies score, log of mechanical ventilation, inotrope, and anesthesia duration, and log of cumulative midazolam and hydrocortisone dose were also associated with MABC-2 scores (p < 0.1). Cumulative fentanyl dose was not associated with composite MABC-2 scores on multiple linear regression. Higher cumulative fentanyl dose was associated with decreased socioemotional problems based on caregiver's response on CBCL/1.5-5.5 t-scores driven by fewer symptoms of depression. The McMaster Family Assessment Device general functioning scale score, maternal age, GA, log of total parenteral nutrition days, patent ductus arteriosus requiring treatment, and log of inotrope hours were also associated with CBCL/1.5-5.5 t-scores (p < 0.1). Cumulative fentanyl dose (p = 0.039) and family dysfunction score (p = 0.002) remained significant after controlling for covariates on multiple linear regression. Conclusion: Cumulative fentanyl dose during neonatal intensive care did not correlate with 5-year motor, cognitive, or language outcomes after controlling for other variables. Fentanyl dose was associated with caregiver reported total socioemotional problems on the CBCL/1.5-5.5 on multivariate modeling. Additional long-term studies are needed to fully elucidate the safety of fentanyl in very preterm neonates.

Know the Code: Medications for Resuscitation in Neonates.

Resuscitations in the delivery room or the nursery cause significant stress for caregivers. Diligent preparation will improve the efficacy and safety of life-saving interventions and increase staff comfort. When establishment of an airway and delivery of positive pressure ventilation and chest compressions fail to result in return of spontaneous circulation, pharmacotherapeutic interventions should be considered. Epinephrine is first-line pharmacotherapy for severe bradycardia or cardiac arrest, increasing coronary arterial pressure and blood flow during chest compressions. Despite limited data regarding dosing and efficacy, the first dose of epinephrine may be delivered through the endotracheal tube during attainment of venous access (preferably a low-lying umbilical venous catheter in the delivery room). Intravenous dosing is preferred, and any facility caring for newborns must ensure optimized logistics including readily available dosing guidance and optimal flush volumes. After provision of epinephrine, additional medications may be considered, especially for resuscitations occurring outside of the immediate perinatal period, including normal saline, glucose, adenosine, atropine, and calcium. Clinicians must understand the indications, dosing, and monitoring parameters for these medications and ensure rapid availability for resuscitation. Every second truly counts in a neonatal resuscitation, and optimal understanding and preparation will ensure delivery of pharmacotherapy to optimize both patient outcomes and staff comfort.

Pharmacologic Analgesia and Sedation in Neonates.

Chronic pain and agitation in neonatal life impact the developing brain. Oral sweet-tasting solutions should be used judiciously to mitigate behavioral responses to mild painful procedures, keeping in mind that the long-term impact is unknown. Rapidly acting opioids should be used as part of premedication cocktails for nonemergent endotracheal intubations. Continuous low-dose morphine or dexmedetomidine may be considered for preterm or term neonates exhibiting signs of stress during mechanical ventilation and therapeutic hypothermia, respectively. Further research is required regarding the pharmacokinetics, pharmacodynamics, safety, and efficacy of pharmacologic agents used to mitigate mild, moderate, and chronic pain and stress in neonates.

The Impact of Dexmedetomidine Initiation on Cardiovascular Status and Oxygenation in Critically ill Neonates.

Dexmedetomidine is being increasingly used as a primary or adjunctive sedative agent in neonates. There are a paucity of high-quality, high-resolution physiologic data during administration, despite significant potential cardiorespiratory effects. Term and preterm infants admitted between January 2018 and July 2020 were screened for dexmedetomidine exposure. Prospectively recorded vital signs (heart rate, oxygenation, arterial blood pressure) were cross-matched with pharmacy records to identify infants with data available 24 h before and 48 h after drug initiation. Vital sign data were processed via a standardized pipeline to (a) remove missing data, (b) obtain baseline averages of vital signs for 24 h preceding dexmedetomidine, and (c) calculate the hourly mean deviation from the baseline for the 48 h following initiation of dexmedetomidine. Infants were clustered by postmenstrual age (preterm ≤ 35 weeks; term > 35 weeks). 72 infants were identified with mean gestational age of 32 weeks and mean ± SD birth weight of 1976 ± 1341 g. Although both groups of infants experienced bradycardia, heart rate in term infants dropped faster and reached a nadir 5 beats per minute lower, before converging at a common deviation of - 10 beats per minute. No hypo- or hypertension was noted in either group. Unexpected instability of oxygenation occurred in a subset of preterm infants, requiring escalation of respiratory support. Administration of dexmedetomidine results in differential timing and magnitude of bradycardia in term and preterm infants, no major impact on blood pressure, and a surprising instability of oxygenation in preterm infants, requiring increased ventilatory support. Further investigation is warranted.