Bronchopulmonary dysplasia is a morbidity of prematurity with implications into adulthood on respiratory and neurologic health. Multiple risk factors contribute to the development of bronchopulmonary dysplasia leading to examination of various strategies of prevention. Systemic corticosteroids are one prevention strategy with a large body of data, creating an ongoing controversy regarding the risks and benefits of therapy. Careful consideration of the available data along with the clinical characteristics of the individual infant is required before using this powerful therapy.

Chronic pain and agitation can complicate the clinical course of critically ill infants. Randomized controlled trials of analgesia and sedation in neonatal intensive care have focused on relatively short durations of exposure. To date, clinicians have few options to treat chronic visceral pain and hyperalgesia. Gabapentin has emerged as a common therapy for a diverse group of pain syndromes and neurologic conditions in adults. In neonates, case reports and series describe the successful treatment of visceral hyperalgesia arising from gastrointestinal insults with or without concomitant neurologic morbidities. Additionally, a case report and series describe the utility of gabapentin for neonatal abstinence syndrome refractory to standard pharmacotherapy. The adverse effect profile of gabapentin, most notably bradycardia and sedation, compares favorably to alternative analgesics and sedatives. However, the long-term impacts of prolonged gabapentin therapy have not been studied. Therefore, candidates for therapy must be selected carefully, and response must be assessed objectively. Future studies must assess the short-term and long-term benefits and risks of gabapentin compared to standard therapies for chronic pain and agitation in infants and refractory neonatal abstinence syndrome.

Delirium is a frequent complication of critical illness in adult and pediatric populations and is associated with significant morbidity and mortality. Little is known about the incidence, risk, symptoms, or treatment of delirium in the NICU. Only 4 cases of NICU delirium have been reported, but many pediatric studies include infants. The Cornell Assessment of Pediatric Delirium tool has been validated in neonatal and infant populations for identification of delirium. Initial treatment should focus on identification and reversal of the cause, with pharmacologic management reserved for patients with symptoms that do not resolve or that significantly impact medical care. Routine use of intravenous haloperidol should be avoided because of the high incidence of serious adverse effects, but it may be considered in patients with significant symptoms who are unable to take oral medications. Atypical antipsychotics (olanzapine, quetiapine, and risperidone) appear to be efficacious with a low incidence of adverse effects. Risperidone has weight-based dosing and a liquid dosage form available, making it a good option for use in the NICU. Additional data from large cohorts of NICU patients routinely screened for delirium, and treated as indicated, are needed.

Hypoxic-ischemic encephalopathy (HIE) remains a significant source of long-term neurodevelopmental impairment despite overall improvements in survival without disability in neonates who undergo therapeutic hypothermia. Each phase in the evolution of hypoxic-ischemic injury presents potential pharmacologic targets for neuroprotective agents. Melatonin is a promising emerging therapy for early phases of ischemic injury, but utility is currently limited by the lack of pharmaceutical-grade products. Magnesium has been extensively studied for its neuroprotective effects in the preterm population. Studies in neonates with HIE have produced mixed outcomes. Erythropoietin use in HIE with or without therapeutic hypothermia appears to be safe and may provide additional benefit. Dexmedetomidine, N-acetylcysteine, xenon, and topiramate all have promising animal data, but need additional human trials to elucidate what role they may play in HIE. Frequent review of existing literature is required to ensure provision of evidence-based pharmacologic agents for neuroprotection following HIE.

Hypotension is a common problem in neonates with complex underlying pathophysiology. Although treatment of low blood pressure is common, clinicians must use all available information to target neonates with compromised perfusion. Pharmacotherapy should be tailored to the specific physiologic perturbations of the individual neonate. Dopamine is the most commonly utilized agent and may be the most appropriate agent for septic shock with low diastolic blood pressure. However, alternative therapies should be considered for other etiologies of hypotension, including milrinone and vasopressin for persistent pulmonary hypertension of the newborn and dobutamine for patent ductus arteriosus. Additional studies are required to refine the approach to neonatal hypotension and document the long-term outcomes of treated neonates.

Neonatal infections result in significant morbidity and mortality. Antibiotics are vital for the treatment of infections but disrupt the neonatal microbiome, put the infant at risk for an adverse drug reaction, and may lead to the development of antibiotic resistance. Immediately after birth, clinicians must determine which infants require empiric antibiotics. Online risk stratification tools may provide a superior approach to decision trees. In infants who require empiric therapy for early-onset sepsis, ampicillin and an aminoglycoside with dosing based on recent pharmacokinetic studies represents the most appropriate first-line agents; third-generation cephalosporins should be reserved for patients with a high likelihood of Gram-negative meningitis. An antistaphylococcal penicillin and gentamicin should be utilized for suspected late-onset sepsis. Vancomycin and other broad-spectrum agents are reserved for patients with a history of resistant organisms. Antibiotic duration should be guided by understanding the clinical indications and obtaining the necessary cultures appropriately (i.e., adequate volume blood cultures). In the absence of a positive culture, antibiotic duration should often be limited. Individual institutions should leverage a multidisciplinary, interprofessional team to identify opportunities for antimicrobial stewardship. A collaborative, transparent system is required to change unit culture and generate a sustained impact on antibiotic utilization with optimal patient outcomes.

Parenteral nutrition (PN) is frequently required by extremely preterm infants due to gastrointestinal immaturity and complications of prematurity. Parenteral nutrition-associated cholestasis (PNAC) and intestinal failure-associated liver disease (IFALD) are common complications of prolonged PN. Plant-based intravenous lipid emulsions, containing proinflammatory omega-6 fatty acids and phytosterols, may contribute to these conditions as well as other comorbidities such as bronchopulmonary dysplasia and retinopathy of prematurity. Intravenous lipid emulsions containing animal-based fats, such as fish oil, contain fewer proinflammatory omega-6 fatty acids and more anti-inflammatory omega-3 fatty acids and antioxidants. SMOFlipid, recently Food and Drug Administration (FDA)-approved for adult use, is a blend of plant- and animal-based lipid emulsions with a favorable omega-6:omega-3 ratio that may prevent the development and progression of PNAC/IFALD in infants. Careful review of data supporting this alternative intravenous lipid emulsion is required prior to widespread use in neonatal intensive care.

Neonatal abstinence syndrome (NAS) from in utero opioid exposure has reached epidemic levels in the United States. Although nonpharmacologic therapies form the foundation of care, many neonates require pharmacotherapy. Morphine represents the most widely used first-line agent and effectively treats the symptoms of withdrawal. However, methadone or buprenorphine may facilitate earlier discharge. Although phenobarbital is traditionally used when opioids fail, clonidine may be a more appropriate adjunctive agent to minimize negative neurodevelopmental impact. Consideration of the available data allows hospitals to generate effective pharmacologic strategies to manage NAS while further research continues.

Endotracheal intubation, a common procedure in neonatal intensive care, results in distress and disturbs physiologic homeostasis in the newborn. Analgesics, sedatives, vagolytics, and/or muscle relaxants have the potential to blunt these adverse effects, reduce the duration of the procedure, and minimize the number of attempts necessary to intubate the neonate. The medical care team must understand efficacy, safety, and pharmacokinetic data for individual medications to select the optimal cocktail for each clinical situation. Although many units utilize morphine for analgesia, remifentanil has a superior pharmacokinetic profile and efficacy data. Because of hypotensive effects in preterm neonates, sedation with midazolam should be restricted to near-term and term neonates. A vagolytic, generally atropine, blunts bradycardia induced by vagal stimulation. A muscle relaxant improves procedural success when utilized by experienced practitioners; succinylcholine has an optimal pharmacokinetic profile, but potentially concerning adverse effects; rocuronium may be the agent of choice based on more robust safety data despite a relatively prolonged duration of action. In the absence of an absolute contraindication, neonates should receive analgesia with consideration of sedation, a vagolytic, and a muscle relaxant before endotracheal intubation. Neonatal units must develop protocols for premedication and optimize logistics to ensure safe and timely administration of appropriate agents.

Caffeine is one of the most commonly utilized medications in the NICU. In preterm infants, short-term and long-term pulmonary and neurodevelopmental benefits of therapy are well documented in the literature. While robust evidence supports the use of standard doses of caffeine for apnea of prematurity or to facilitate successful extubation, much remains unknown regarding the boundaries of efficacy and safety for this common therapeutic agent. Escalating dosing regimens seem to provide additional benefit in select infants, but grave toxicity has also been documented with early utilization of high-dose caffeine. Conflicting data exist surrounding the ideal timing of initiation of therapy. Even the widely adhered to discontinuation point has been challenged by data supporting continued use. Until robust data definitively support change, practice should align with current evidence defining clear, safe, and efficacious dosing and timing of caffeine therapy.