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.

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.

Delirium in the NICU: Risk or Reality?

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.

Nicardipine for the Treatment of Neonatal Hypertension During Extracorporeal Membrane Oxygenation.

Extracorporeal membrane oxygenation (ECMO) is one of the primary reasons systemic hypertension is experienced in hospitalized neonates. Commonly used antihypertensive agents have resulted in significant adverse effects in neonatal and pediatric populations. Nicardipine is a desirable option because of its rapid and titratable antihypertensive properties and low incidence of adverse effects. However, data for use in neonatal ECMO are limited. We conducted a retrospective review of patients less than 44 weeks post-menstrual age who received a nicardipine infusion for first-line treatment of systemic hypertension while on ECMO at our institution between 2010 and 2016. Systolic (SBP), diastolic (DBP), and mean arterial (MAP) blood pressures were evaluated for 48-h after nicardipine initiation. Eight neonates received a nicardipine infusion while on ECMO during the study period. Nicardipine was initiated at a mean dose of 0.52 ( ± 0.22) mcg/kg/min and titrated to a maximum dose of 1.1 ( ± 0.85) mcg/kg/min. The median duration of nicardipine use was 51 (range 4-227) hours. Significant decreases in SBP, DBP, and MAP occurred within one hour of initiation of nicardipine and were sustained through the majority of the 48-h evaluation period. No patients experienced hypotension. Prospective studies are warranted to evaluate the optimal dose, safety, and efficacy of nicardipine in neonates who require ECMO.

Antimicrobial Stewardship in Neonates: Challenges and Opportunities.

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.

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.

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.

Respiratory effects of prolonged prednisolone use in infants with evolving and established Bronchopulmonary dysplasia.

BACKGROUND: Current literature focuses on systemic corticosteroids for prevention of bronchopulmonary dysplasia (BPD) in preterm infants with limited data on use for pulmonary disease after the first month of life. Prednisolone may be a reasonable option for late treatment given its desirable pharmacologic properties and use in other pediatric disease states. AIMS: To characterize a premature population that received an extended prednisolone course and determine the effect on respiratory and anthropometric outcomes over time. STUDY DESIGN: Single-center, retrospective study. SUBJECTS: Preterm infants who received ≥30 days of prednisolone or methylprednisolone for treatment of respiratory complications following preterm birth. OUTCOMES MEASURES: Assessment of pulmonary severity score (PSS), weight, length, and occipital frontal circumference weekly during the first 4 weeks of prednisolone and after discontinuation. RESULTS: Thirty-four infants with a mean gestational age of 26.5 ± 2.5 weeks and birth weight of 846 ± 353 g were identified. Nine patients were on invasive mechanical ventilation and 25 patients were on non-invasive respiratory support at prednisolone initiation. Prednisolone was initiated at a mean post-menstrual age of 41.7 ± 5 weeks and a mean dose of 1.7 ± 0.6 mg/kg/day. A significant decrease in PSS was seen over time (p < 0.001) without rebound following discontinuation. Eleven patients decreased the mode of respiratory support during prednisolone treatment. No significant impact in anthropometric outcomes were identified. CONCLUSION: Prolonged prednisolone use was associated with a sustained decrease in PSS without adverse effects on growth measurements. These results suggest potential benefit of prednisolone on respiratory outcomes in a subset of preterm infants.

Antithrombin Dose Optimization in Extracorporeal Membrane Oxygenation in Infants.

Anticoagulation in extracorporeal membrane oxygenation (ECMO) is challenging, with significant morbidity and mortality associated with thrombotic complications. Unfractionated heparin (UFH) is commonly used, which depends on native antithrombin (AT) function to exert anticoagulant effects. Antithrombin deficiency is common in infants on ECMO and replacement with AT concentrate may be warranted. However, dosing recommendations in this population are limited. We conducted a retrospective review of patients <1 year of age who received recombinant AT (ATryn) while on UFH and ECMO between January 1, 2010 and December 31, 2017. Commonly used dosing equations were assessed to determine their ability to predict postdose AT levels. Patient AT levels were compared with equation-predicted postdose AT levels to determine a correlation. A total of 102 doses in 41 patients were used for analysis. Baseline mean AT level was 43% (±13%) and mean AT doses were 134 units (±58.1 units) or 40.5 units/kg (±18.7 units/kg). Median increase in the AT level was 8% (interquartile range 2-17%) with a mean postdose level of 52.6% (±14.2%). Weight-based dosing poorly correlated with postdose AT levels (r2 = 0.082). Postdose levels were best predicted when using an equation that included desired change in the AT level from baseline, the patient's weight, and added weight from the volume of the ECMO circuit (r2 = 0.427). Prospective studies are needed to evaluate optimal dosing strategies, safety, and efficacy of AT in this population.

Propranolol for the Treatment of Lymphatic Malformations in a Neonate - A Case Report and Review of Literature.

Lymphatic malformations in neonates often manifest as a chylothorax, and although rare, morbidity and mortality can be significant. First-line treatment with medium-chain triglyceride-enriched formulas, or enteric rest with total parenteral nutrition, are not always successful. We describe the case of a premature neonate with trisomy 21 who presented with bilateral pleural effusions and a pericardial effusion that worsened with the initiation of enteral nutrition. Clinical improvement was not seen until the initiation of treatment with oral propranolol at a maximum dosage of 0.5 mg/kg/day divided every 8 hours with extubation 8 days after propranolol initiation. Two case reports have described the use of propranolol in similar patients receiving 2 mg/kg/day; however, our experience is the first to report treatment success at a much lower dose. A review of the literature for alternative medication treatments uncovered numerous case reports and series documenting variable results with incongruent definitions of treatment success in a diverse patient population. The rarity of this disease state makes accrual of patients difficult and more robust treatment data unlikely. Therefore, selection of the optimal adjunctive treatment must be based on individual patient and disease state characteristics as well as safety and efficacy profile of the medication.

Acetaminophen Serum Concentrations in Infants Treated Intravenously for Patent Ductus Arteriosus.

OBJECTIVE: Although acetaminophen has emerged as a therapeutic option for treating hemodynamically significant patent ductus arteriosus (PDA) in preterm infants, limited data exist on pharmacodynamics. The objective of this research is to report serum acetaminophen concentrations at steady state in infants treated with intravenous acetaminophen for PDA and to examine associations with clinical outcomes. METHODS: This retrospective study evaluated all infants admitted during the study period who received intravenous acetaminophen for the treatment of PDA. Acetaminophen dosing was 15 mg/kg every 6 hours. A serum acetaminophen concentration was obtained 4 hours after the eighth dose. Associations between serum concentrations and efficacy, assessed by ductal constriction on echocardiogram, and safety, assessed by serum creatinine and hepatic transaminases, were explored using simple linear regression. RESULTS: A total of 36 infants were included, with a median birth weight of 720 g (IQR 585-895 g) and a median gestational age of 25 weeks (IQR 24-26 weeks). The median acetaminophen concentration in the cohort was 12.3 mg/L (IQR 6.7-16.5 mg/L; range, 1.1-29.0 mg/L). Serum acetaminophen concentrations did not correlate with infant demographics, hepatic transaminases during treatment, or duct size at treatment completion. We observed ductal closure across a wide range of serum acetaminophen concentrations. CONCLUSIONS: We did not identify an association between acetaminophen serum concentrations following intravenous therapy and ductal response or hepatic toxicity.

Acetaminophen for Patent Ductus Arteriosus in Extremely Low-Birth-Weight Neonates.

OBJECTIVE: Although non-steroidal anti-inflammatory drugs (NSAIDs) are the current standard therapy for the treatment of patent ductus arteriosus (PDA), many neonates have contraindications to receiving or may fail NSAID therapy. To avoid surgical ligation, these patients may benefit from an alternative therapy. The objective of this research is to report the efficacy and safety of acetaminophen for the treatment of PDA in a cohort of premature neonates. METHODS: Demographics and clinical course were retrospectively evaluated for all neonates admitted during the study period who received acetaminophen for the treatment of PDA. Initial acetaminophen dosing was 15 mg/kg every 6 hours (88% intravenous). Efficacy was analyzed from ductal constriction on echocardiogram as well as need for further PDA treatment. Markers of hepatic and renal function as well as respiratory support and neonatal morbidities were evaluated to describe the safety of acetaminophen. RESULTS: Forty-one neonates were identified with a median birth weight of 760 g (IQR 614-948 g) and median gestational age of 25 weeks (IQR 24-27 weeks). Treatment was initiated at a median postnatal age of 15 days (IQR 8-19 days) for a median duration of 7 days (IQR 6-10 days). Twenty-seven neonates (66%) required no further PDA treatment, with echocardiographic PDA closure documented in 10 neonates (24%) and reduced ductal size in 15 neonates (37%). No clinically significant adverse effects attributable to acetaminophen therapy were detected. CONCLUSIONS: Most patients in this study responded to acetaminophen treatment for PDA, indicating that this therapy may be an option for extremely low-birth-weight neonates in order to avoid surgical ligation.