The research gap in chronic paediatric pain: A systematic review of randomised controlled trials.

BACKGROUND AND OBJECTIVE: Chronic pain is associated with significant functional and social impairment. The objective of this review was to assess the characteristics and quality of randomized controlled trials (RCTs) evaluating pain management interventions in children and adolescents with chronic pain. METHODS: We performed a systematic search of PubMed, Embase and the Cochrane Library up to July 2017. We included RCTs that involved children and adolescents (3 months-18 years) and evaluated the use of pharmacological or non-pharmacological intervention(s) in the context of pain persisting or re-occurring for more than 3 months. Methodological quality was evaluated using the Cochrane Risk of Bias (ROB) Tool. RESULTS: A total of 58 RCTs were identified and numbers steadily increased over time. The majority were conducted in single hospital institutions, with no information on study funding. Median sample size was 47.5 participants (Q1,Q3: 32, 70). Forty-five percent of RCTs included both adults and children and the median of the mean ages at inclusion was 12.9 years (Q1,Q3: 11, 15). Testing of non-pharmacological interventions was predominant and only 5 RCTs evaluated analgesics or co-analgesics. Abdominal pain, headache/migraine and musculoskeletal pain were the most common types of chronic pain among participants. Methodological quality was poor with 90% of RCTs presenting a high or unclear ROB. CONCLUSIONS: Evaluation of analgesics targeting chronic pain relief in children and adolescents through RCTs is marginal. Infants and children with long-lasting painful conditions are insufficiently represented in RCTs. We discuss possible research constraints and challenges as well as methodologies to circumvent them. SIGNIFICANCE: There is a substantial research gap regarding analgesic interventions for children and adolescents with chronic pain. Most clinical trials in the field focus on the evaluation of non-pharmacological interventions and are of low methodological quality. There is also a specific lack of trials involving infants and children and adolescents with long-lasting diseases.

Fluconazole use and safety in the nursery.

Fluconazole is a triazole antifungal agent that is widely used in the nursery. It is available in both intravenous and oral formulation, and is active against most of the fungal pathogens that require treatment when retrieved from culture samples in neonatal intensive care units. Although clinical use has been wide for over 15 years, there have been small safety and efficacy studies completed in young infants. Randomised clinical trials assessing effectiveness of this agent in prevention of systemic fungal infections in neonates have been published in the last decade, and one large additional randomised study has been recently completed. Nevertheless, a certain degree of uncertainty still exists regarding the kinetics and appropriate dosing of this agent in premature and term infants, as well as regarding safety. Areas of poignant debate include the feasibility of loading dose strategies, appropriate dosages in the early days of life in the different subgroups of preterm infants, and long-term safety of fluconazole administered in prophylaxis during the first weeks of life in extremely premature infants. This paper reviews the most recent evidence on fluconazole and its role in the NICU settings.

Neonatal fungal infections: when to treat?

Candida infections are a major cause of morbidity and mortality in neonatal intensive care units. Mortality following Candida bloodstream infections is as high as 40%, and neurodevelopmental impairment is common among survivors. Because invasive fungal infections are common and extremely difficult to diagnose, empirical treatment with antifungal therapy should be considered in high-risk, low-birth-weight infants who fail to quickly respond to empirical antibacterial treatment. Risk factors to consider when deciding to administer empirical antifungal therapy include: prior exposure to third-generation cephalosporins, extreme prematurity, and presence of central venous catheters.

Clinical characteristics and response to prophylactic fluconazole of preterm VLBW neonates with baseline and acquired fungal colonisation in NICU: data from a multicentre RCT.

BACKGROUND: Fungal colonisation by Candida spp. affects a high proportion of VLBW neonates in NICU. However, few data are available on the clinical characteristics of colonisation in preterm infants who are colonised at baseline via vertical transmission, compared to preterms who become colonised during their stay in NICU via horizontal transmission. MATERIAL AND METHODS: We reviewed the database of a multicentre, randomised trial of prophylactic fluconazole in VLBW neonates conducted in 8 Italian NICUs in the years 2004 and 2005 (Manzoni et al., NEJM 2007;356(24):2483-95). Per the protocol, all enrolled infants underwent weekly surveillance cultures from birth till discharge. We investigated the frequency of the two different modalities of Candida colonisation in this population, as well as the clinical and outcome characteristics possibly related to them. RESULTS: Overall, Candida colonisation affected 54 of 336 infants (16.1%). Baseline (i.e., detected <3(rd) day of life) colonisation affected 16 (4.7%), and acquired 38 (11.4%), of the 54 colonised preterms. Infants with baseline colonisation had significantly higher birth weight (1229 ± 28 g vs. 1047 g ± 29, p = 0.01) and gestational age (30.2 wks ± 2.7 vs. 28.5 wks ± 2.6, p = 0.01), and were significantly more likely to limit progression from colonisation to invasive Candida infection when fluconazole prophylaxis was instituted (21.6% vs. 42.7%, p = 0.009). Isolation of C. parapsilosis was significantly more frequent in infants with acquired colonisation. CONCLUSIONS: Infants with baseline and acquired colonisation differ for demographics characteristics and for their response to fluconazole prophylaxis. This information may be useful for targeting more accurate management strategies for these two different groups of colonised preterms in NICU.

Neonatal cutaneous disseminated aspergillosis in a preterm extremely-low-birth-weight infant with favourable outcome at 3-year follow-up: a case report.

Invasive disseminated neonatal aspergillosis is an uncommon disease, with only scattered reports in literature in the last few years. Here we report on a 25-week gestational age, 730 g at birth preterm female infant who developed on day-of-life 10 multiple cutaneous exhulcerative lesions in her right arm, trunk and abdomen. Early recognition and diagnosis of these lesions as a due to cutaneous initial symptom of cutaneous disseminated aspergillosis, as well as prompt treatment with Liposomal amphotericin B + Itraconazole, secured successful recovery from the systemic infection. Skin lesions healed without any surgical treatment. The infant was discharged in good health. Long-term follow-up at three years of age revealed normality of all neurodevelopmental and cognitive parameters. To our knowledge, this is one of the very few cases of survival, free from sequelae, for a preterm infant affected by neonatal cutaneous disseminated aspergillosis.

Early and late onset sepsis in very-low-birth-weight infants from a large group of neonatal intensive care units.

BACKGROUND: Very-low-birth-weight (VLBW, <1500 g birth weight) infants are at high risk for both early- and late-onset sepsis. Prior studies have observed a predominance of Gram-negative organisms as a cause of early-onset sepsis and Gram-positive organisms as a cause of late-onset sepsis. These reports are limited to large, academic neonatal intensive care units (NICUs) and may not reflect findings in other units. The purpose of this study was to determine the risk factors for sepsis, the causative organisms, and mortality following infection in a large and diverse sample of NICUs. METHODS: We analysed the results of all cultures obtained from VLBW infants admitted to 313 NICUs from 1997 to 2010. RESULTS: Over 108,000 VLBW infants were admitted during the study period. Early-onset sepsis occurred in 1032 infants, and late-onset sepsis occurred in 12,204 infants. Gram-negative organisms were the most commonly isolated pathogens in early-onset sepsis, and Gram-positive organisms were most commonly isolated in late-onset sepsis. Early- and late-onset sepsis were associated with increased risk of death controlling for other confounders (odds ratio 1.45 [95% confidence interval [CI] 1.21,1.73], and OR 1.30 [95%CI 1.21, 1.40], respectively). CONCLUSIONS: This is the largest report of sepsis in VLBW infants to date. Incidence for early-onset sepsis and late-onset sepsis has changed little over this 14-year period, and overall mortality in VLBW infants with early- and late-onset sepsis is higher than in infants with negative cultures.

Sepsis in young infants with congenital heart disease.

BACKGROUND: We sought to describe the incidence, pathogen distribution, and mortality associated with blood culture-proven sepsis in young infants with congenital heart disease (CHD) admitted to a neonatal intensive care unit (NICU). METHODS: Cohort study of all blood cultures obtained from infants with CHD between 4 and 120 days of age cared for in 250 NICUs managed by the Pediatrix Medical Group in the United States between 1996 and 2007. RESULTS: Of 11,638 infants with CHD, 656 (6%) had 821 episodes of sepsis: a cumulative incidence of 71/1000 admissions. Gram-positive organisms were the most common cause (64%), and coagulase-negative Staphylococcus and Staphylococcus aureus were the most frequently isolated species. On multivariable regression, infants with sepsis were more likely to die compared to infants with sterile blood cultures (odds ratio [OR] = 1.53 [95% confidence interval: 1.09, 2.13]). Infants with Gram-negative bacteraemia and candidaemia were more likely to die than infants with sterile blood cultures (OR = 2.01 [1.20, 3.37], and OR = 3.18 [1.60, 6.34], respectively). CONCLUSION: Infants with CHD have a high incidence of culture-proven sepsis, especially with staphylococcal organisms. Gram-negative bacteraemia and candidaemia are strongly associated with increased mortality in this group of young infants.

Invasive group A streptococcal infection in children: clinical manifestations and molecular characterization in a French pediatric tertiary care center.

Invasive group A streptococcal (GAS) infections have a broad and evolving clinical spectrum, associated with various GAS genotypes and/or virulence factors that are only poorly described in children. We aimed to assess the clinical and molecular characteristics of invasive GAS infections in 28 children admitted from 2000 to 2007 at a large French pediatric tertiary care center. The GAS isolates were characterized molecularly by emm-typing and by the determination of the main virulence factors: speA, speB, speC, smeZ-1, ssa, sic, and silC. The median age of the children was 2.9 years. Osteoarticular infection (OAI) was the main clinical manifestation (n=15/28, 53%). emm-1 predominated (n=10/28), followed by emm-12, 3, and 4. No significant correlation was found between emm type and clinical manifestations, but emm-1 predominated in cases of OAI (n=7/15) and was associated with speA, speB, smeZ-1, and sic virulence factor genes. In this pediatric study, we describe a predominance of OAI associated with emm-1 GAS. Further larger international pediatric studies, including host immunity evaluation, are needed in order to better assess the pathogenesis of GAS infection in children.