Reviews on Recent Clinical Trials - Volume 12, Issue 4, 2017

Background: The evaluation and management of infants with neonatal abstinence syndrome (NAS), the constellation of opioid withdrawal specific to newborns, have received renewed attention over the past decade during a new epidemic of opioid use, misuse, abuse, and dependence. Infants with NAS often endure long and costly hospital stays. Objective: We aim to review recent literature on the management and outcomes of infants with, and at risk for, opioid withdrawal. Methods: We reviewed articles indexed in PubMed over the past 5 years that examined interventions and/or outcomes related to the management of infants with NAS. Thirty-seven studies were included in our review comprising 8 categories: 1) identification of infants at risk for NAS, 2) prenatal factors, 3) evaluation of signs and symptoms, 4) non-pharmacologic care, including rooming-in and breastfeeding, 5) standardization of traditional protocols, 6) pharmacologic management, 7) alternative treatment approaches, and 8) long-term outcomes. Results: Non-pharmacologic interventions, standardization of traditional protocols, and alternative treatment approaches were all associated with improved outcomes. Lengths of stay were generally lowest in the studies of non-pharmacologic interventions. Patients exposed to buprenorphine in utero tended to have better short-term outcomes than those exposed to methadone. Longer-term outcomes for infants with NAS appear to be worse than those of control groups. Conclusion: The current epidemic necessitates both continued research, and the application of new evidence-based practices in the assessment and treatment of newborns exposed to opioids in utero. Projects focused on non-pharmacologic interventions appear to hold the most promise.

Background: The thirty-year-old term “apparent life-threatening event” (ALTE) is difficult to apply in clinical practice and research. The American Academy of Pediatrics now defines these events as brief resolved unexplained events (BRUEs), stratifies infants based on the risk of recurrence or of a serious underlying condition, and offers evidence-based management recommendations for infants at lower-risk. Objective: To review recent ALTE literature as it relates to BRUEs. Method: Articles were identified by searching several clinical databases. English-language articles from January 2006 to August 2016 that address ALTEs or BRUEs were included. Results: Significant variation exists in the evaluation and management of patients diagnosed with BRUE. Research demonstrates low utility of most diagnostic testing, including prolonged cardiorespiratory monitoring, in the well-appearing infant without an obvious etiology. Risk factors for recurrent adverse events or significant underlying pathology include young age, prematurity, and presence of multiple events. There is little evidence to provide guidance for the management of higher-risk infants. Conclusion: BRUE is a diagnosis of exclusion to be applied when there is no apparent etiology after performing an appropriate history and physical examination. Lower-risk infants should not undergo routine diagnostic testing and should not be admitted solely for cardiorespiratory monitoring. Higherrisk infants are more likely to benefit from diagnostic testing and admission; however, routine screening testing is unnecessary, and the history and physical should guide the clinician's approach. Prospective research is needed to understand the incidence of BRUEs, outcomes in lower and higher-risk infants, and the utility of diagnostic testing in higher-risk infants.

Background: Despite development of risk stratification tools decades ago, the best strategy for evaluation and management of young infants with fever without a clear source remains uncertain. Objective: To describe the variability in current practice and review recently published evidence in three key areas: inflammatory markers were used as a tool for risk stratification, impact of viral testing, and optimal observation time on antibiotics. Method: Articles were identified using PubMed, Scopus, and Cochrane databases and via experts. Abstracts were screened and potential articles underwent full review if they focused on febrile infants 0- 90 days with fever without a source and outcomes for key topics. Results: Thirty-two articles were included. Recent studies show that variability exists for most aspects of evaluation and management. C reactive protein and procalcitonin (PCT) perform poorly for identification of serious bacterial infections (SBIs). However, PCT has good diagnostic accuracy for detection of invasive bacterial infections (IBIs), such as bacteremia and meningitis. When PCT is combined with urinalysis and clinical appearance in the Step-by-Step method, the sensitivity for detection of IBI is 92% for infants > 21 days of age. Infants with lab-confirmed viral infection were found to have reduced risk for SBI. Blood culture yield for true pathogens was the highest in the first 12-36 hours after incubation. Conclusion: Recent studies suggest viral testing and inflammatory markers (specifically PCT) can help better stratify young febrile infants at risk for IBIs. Infants who are deemed low risk may benefit from shorter observation times and tailored or discontinued antibiotic therapy.

Background: Viral bronchiolitis is a common cause of hospitalization in young children, but despite a variety of therapeutic options, the mainstay of treatment remains supportive care. Objective: To examine the most recent evidence for supportive care measures and pharmacologic options in the treatment of bronchiolitis in the hospital setting. Method: MEDLINE search with expert medical librarian for publications on management and therapies for bronchiolitis. Results: Evidence does not support the use of bronchodilators, racemic epinephrine, deep suctioning, systemic corticosteroids, or antibiotics in the absence of a concomitant bacterial infection, as these treatments do not change the course of illness or shorten length of stay (LOS). Nebulized hypertonic saline is not routinely recommended, though it may provide some benefit for patients with anticipated prolonged LOS. Continuous pulse oximetry should not be routinely used in stable patients as it may be associated with longer LOS. Supplemental oxygen should be used to maintain oxyhemoglobin concentrations ≥90%, a level lower than what many clinicians may have used previously. Current evidence suggests high-flow nasal cannula may reduce intubation rate, but its effect on LOS is unclear. Intravenous or nasogastric tube hydration should be used when oral hydration is not sufficient. Conclusion: Overall, bronchiolitis remains a self-limited disease whose mainstay of therapy is supportive care.

Background: Despite declining rates of community acquired pneumonia (CAP) in children, complicated pneumonia has been on the rise in the last two decades. The management of complicated pneumonia is challenging and continues to be an area of investigation. Despite recently published guidelines, many gaps exist and recent studies attempt to answer challenging questions. Objective: The aim was to review recently published literature to inform the clinician about the most up to date management of complicated pneumonia in children. Methods: Using Medline, a search of the medical literature was conducted in order to find relevant clinical trials and review articles published in the last 5 years. Results: Narrow spectrum antibiotics including ampicillin and azithromycin remain important first line agents, but directed therapy towards causative pathogens is the ideal standard practice. Novel DNA isolation technologies hold promise for raising the diagnostic yield of pleural fluid. Surgical interventions are often required and new literature further supports the use of fibrinolytics and minimally invasive chest tube thoracostomy. Not to be overlooked is the importance of supportive measures including oxygen therapy and adequate fluid, electrolyte and nutrition support. The use of other adjunctive therapies such as steroids in pediatric complicated pneumonia remains controversial. Conclusion: Recent studies have shown promise in establishing best practices for evaluation and management of complicated pneumonia in children. Despite these robust efforts however, many areas are in need of future inquiry and prospective studies could help to better understand the optimal therapeutic and diagnostic options for children with this common and persistent childhood illness.

Background: Pediatric osteoarticular infections are relatively rare but important diseases to identify early and treat appropriately in order to avoid associated acute complications or long-term morbidity. Objective: To review the current epidemiology and etiology of pediatric osteoarticular infections as well as recent advances in the diagnosis and treatment of these infections. Methods: We searched PubMed (MEDLINE) and Scopus databases for potentially relevant publications in the past 5 years. Results: Bacterial epidemiology and antimicrobial resistance profiles vary greatly worldwide, although Staphylococcus aureus, streptococci and Kingella kingae are the predominant pathogens. There is emerging evidence supporting the role of PCR assays for pathogen detection. Conclusion: Current data suggest that most children with osteoarticular infections can be successfully transitioned to oral antibiotics after having received at least several days of intravenous therapy, undergone removal of significant infectious foci and having demonstrated clinical improvement with down trending inflammatory markers. The optimal length and route of antimicrobial therapy have not been fully elucidated and should depend on individual patient factors, the virulence of the pathogen and the monitored clinical and laboratory response to therapy.

Background: Urinary Tract Infection (UTI) is a common cause of bacterial infection in young children, and accounts for a significant number of pediatric hospitalizations. Objective: To review recent publications focusing on the care of children hospitalized with their first febrile UTI. Methods: A PubMed search was performed including publications from 2011-2016 on first febrile UTI in childhood. Abstracts were reviewed for being relevant to the care of hospitalized children and their follow-up. Relevant articles underwent full review by all authors and articles excluded from results included those without novel data analysis, primary improvement-based reports and studies with poor design or analysis. Included articles were categorized as “diagnosis”, “management”, “imaging” or “follow-up”. Results: Of 406 articles initially identified, 40 studies were included. One technical report with a systematic review was also included. Major topics addressed included the role of urinalysis in screening for UTI, use of parenteral antimicrobial therapy, the role of antimicrobial prophylaxis in prevention of recurrent UTI, and ideal follow-up and imaging approach following diagnosis of febrile UTI. Conclusion: Recent literature on first febrile UTI addresses a broad range of areas regarding the care of hospitalized children, though some questions remain unanswered. Overall, studies support increased attention to the potential risks, expense and invasiveness of various approaches for evaluation. Proposed updates to practice included: utilization of urinalysis for screening and diagnosis, transitioning to oral antimicrobials based on clinical improvement and limiting the routine use of voiding cystourethrogram and antimicrobial prophylaxis.

Background: Acute pain in hospitalized pediatric patients is prevalent. Recent shifts in the paradigm of pediatric acute pain management focus less on reliance on opioids, due to their adverse side effects and risk of dependence, and more on multimodal pain management. Objective: We sought to review the most recent studies on acute pain management in hospitalized pediatric patients. Method: We searched the Cochrane Database and PubMed for articles published in the past five years regarding the treatment of acute pain in pediatric patients focusing on large randomized or quasirandomized controlled trials, cohort trials, and meta-analyses. Results: We categorized results into non-pharmacological, localized, non-opiate pharmacological, and opiate based therapies. Recent studies show that environmental and non-pharmacological methods of pain management are efficacious in infants. School aged children benefit from active distraction more than passive distraction. Needleless methods of introducing lidocaine locally alleviate the pain associated with many procedures to which hospitalized children are exposed. The shift towards use of nonopiate pharmacology focuses on novel means of utilizing older medications, such as intravenous parecoxib, inhaled methoxyflurane, and sublingual ketorolac or tramadol and the avoidance of codeine. Conclusion: Acute pediatric pain management has changed to emphasize multimodal and multidisciplinary therapy. In all children, non-pharmacological therapies should be employed routinely. Given the myriad tools available, pediatric acute pain services have developed in order to integrate more advanced treatments such as nerve blocks and infusions of centrally acting pain modulators.

Background: Fluid and electrolyte therapy is an important component in the care of the hospitalized child. Previous pediatric guidelines have followed the Holliday-Segar method of calculating and delivering maintenance IV fluids, using hypotonic fluids in maintenance therapy. However, research demonstrates that hypotonic fluids can lead to iatrogenic hyponatremia and that isotonic fluid is a safer alternative. Objective: To provide the ideal approach to intravenous (IV) fluid use in the hospitalized child and determine the safety and effectiveness of isotonic maintenance fluid therapy. Method: We searched PubMed, Medline, Cochrane Controlled Clinical Trials Register, and Clinical- Trials.gov for potentially relevant publications from the last five years (2011 to July 2016) with an emphasis on randomized control trials (RCTs) and contemporary evidence-based treatment guidelines. Results: For maintenance IV fluids, isotonic solutions decreased risk of hyponatremia and did not increase risk of hypernatremia. Some studies demonstrate increased ADH production or hyponatremia on admission for hospitalized patients. Conclusion: While there is no ideal composition of maintenance IV fluids for all children, isotonic fluids are safer than hypotonic fluids for use as maintenance in hospitalized children due to the decreased risk of iatrogenic hyponatremia. This article also provides recommendations for other types of fluid management in the inpatient pediatric population.

Background: Concerns about the costs and quality of hospital care have led to increased interest in hospital readmissions in children. Children with medical complexity account for high proportions of inpatient utilization and have a higher risk of hospital readmission. Objective: To identify studies of discharge interventions to prevent hospital readmissions in children with medical complexity. Methods: We conducted a search to identify studies of discharge interventions. Included studies 1) described an intervention or modifiable risk factor around the time of hospital discharge 2) included pediatric patients with chronic illness and/or medical complexity and 3) reported subsequent hospital utilization. Results: We identified ten studies testing the following interventions: multi-faceted discharge bundle (including medication review, discharge education, and follow-up appointments) (s=1), post-discharge follow-up clinic visits (s=3), post-discharge phone calls (s=2), intensive follow-up interventions for very low birth weight infants (s=2), and education interventions in children hospitalized with asthma (s=2). Four studies reported reductions in readmissions. The discharge bundle correlated with an 11.1% decrease in 30-day readmission (9.9% vs. 8.8%, p<0.05). All three studies of post discharge follow-up clinic visits reported a decrease in 30-day readmission risk among children with follow-up scheduled within 30 days, though one study also reported that medically complex children with follow- up within three days had increased readmission risk. Conclusion: Evidence supporting discharge interventions for children with medical complexity is limited. Multi-faceted discharge interventions and post-discharge clinic visits may be effective.