(See the editorial commentary by Bagni and Whitby, on pages 873–4.)
Background. Candidemia is a severe invasive fungal infection with high mortality. Recognition of Candida species is mediated through pattern recognition receptors such as Toll-like receptors (TLRs). This study assessed whether genetic variation in TLR signaling influences susceptibility to candidemia.
Methods. Thirteen mostly nonsynonymous single nucleotide polymorphisms (SNPs) in genes encoding TLRs and signaling adaptors MyD88 and Mal/TIRAP were genotyped in 338 patients (237 white, 93 African American, 8 other race) with candidemia and 351 noninfected controls (263 white, 88 African American). The SNPs significant in univariate analysis were further analyzed with multivariable logistic regression to determine association with clinical outcomes. Functional consequences of these polymorphisms were assessed via in vitro stimulation assays.
Results. Analyses of TLR SNPs revealed that 3 TLR1 SNPs (R80T, S248N, I602S) were significantly associated with candidemia susceptibility in whites. This association was not found in African Americans, likely due to lower power in this smaller study population. Furthermore, these TLR1 polymorphisms displayed impaired cytokine release by primary monocytes. No associations with susceptibility to candidemia were observed for SNPs in TLR2, TLR4, TLR6, TLR9, MyD88, or TIRAP.
Conclusions. Nonsynonymous SNPs in TLR1 are associated with impaired TLR1 function, decreased cytokine responses, and predisposition to candidemia in whites.
During high frequency oscillatory ventilation (HFOV), bias flow is the continuous flow of gas responsible for replenishing oxygen and removing carbon dioxide (CO2) from the patient circuit. Bias flow is usually set at 20 liters per minute (lpm), but many patients require neuromuscular blockade (NMB) at this flow rate. The need for NMB may be eliminated by increasing the bias flow rate, but CO2 retention is a potential concern. We hypothesize that in a swine model of acute lung injury (ALI), increased bias flow rates will not affect CO2 elimination.
Prospective, randomized, experimental study.
Research laboratory at a university medical center.
Sixteen juvenile swine.
Sixteen juvenile swine (12-16.5 kg) were studied using a saline lavage model of ALI. During HFOV, each animal was ventilated with bias flows of 10, 20, 30, and 40 lpm in random sequence. For 10 animals, power was set at a constant level to maintain PaCO2 50-60 mmHg, and amplitude was allowed to vary. For the remaining 6 animals, amplitude was kept constant to maintain PaCO2 within the same range, while power was adjusted as needed with changes in bias flow. Linear regression was used for data analysis.
Measurements and Main Results
Median overall PaCO2 was 53 mmHg (range: 31-81 mmHg). Controlling for both power and amplitude, there was no statistically significant change in PaCO2 as bias flow varied from 10 to 40 lpm.
Changes in bias flow during HFOV did not affect ventilation. Further clinical investigation is ongoing in infants and children with ALI being managed with HFOV to assess the impact of alterations of bias flow on gas exchange, cardiopulmonary parameters, sedation requirements and other clinical outcomes.
high frequency ventilation; bias flow; carbon dioxide elimination; mean airway pressure; acute lung injury; acute respiratory distress syndrome; oscillation; mechanical ventilation; pediatric; neonate
Neonatal sepsis causes significant morbidity and mortality, especially in preterm infants. Consequently, clinicians are compelled to treat with empirical antibiotics at the first signs of suspected sepsis. Unfortunately, both broad-spectrum antibiotics and prolonged treatment with empirical antibiotics are associated with adverse outcomes including invasive candidiasis, increased antimicrobial resistance, necrotizing enterocolitis, late-onset sepsis, and death. Most common neonatal pathogens are susceptible to narrow-spectrum antibiotics. The choice of antibiotic and duration of empirical treatment are strongly associated with center-based rather than with individual patient risk factors, implying that these choices are modifiable across centers. Thus, clinicians should aim to treat with short courses of narrow-spectrum antibiotics whenever possible, choosing the appropriate antibiotics and treatment duration to balance the risks of potentially untreated sepsis against the adverse effects of treatment in infants with sterile cultures.
neonatal intensive care unit; empirical; antibiotic; sepsis; infection
invasive candidiasis; amphotericin B deoxycholate; flucytosine; fluconazole; voriconazole; posaconazole; micafungin; anidulafungin; caspofungin
We assessed the role of genetic variation in cytokine and cytokine receptor genes in susceptibility and severity of bloodstream infections with Candida species, which revealed a major role for functional polymorphisms in interleukin-10 and interleukin-12p40 in predisposing to persistent fungemia.
Background. Candida bloodstream infections cause significant morbidity and mortality among hospitalized patients. Although clinical and microbiological factors affecting prognosis have been identified, the impact of genetic variation in the innate immune responses mediated by cytokines on outcomes of infection remains to be studied.
Methods. A cohort of 338 candidemia patients and 351 noninfected controls were genotyped for single-nucleotide polymorphisms (SNPs) in 6 cytokine genes (IFNG, IL10, IL12B, IL18, IL1β, IL8) and 1 cytokine receptor gene (IL12RB1). The association of SNPs with both candidemia susceptibility and outcome were assessed. Concentrations of pro- and antiinflammatory cytokines were measured in in vitro peripheral blood mononuclear cell stimulation assays and in serum from infected patients.
Results. None of the cytokine SNPs studied were associated with susceptibility to candidemia. Persistent fungemia occurred in 13% of cases. In the multivariable model, persistent candidemia was significantly associated with (odds ratio [95% confidence interval]): total parenteral nutrition (2.79 [1.26–6.17]), dialysis dependence (3.76 [1.46–8.64]), and the SNPs IL10 rs1800896 (3.45 [1.33–8.93]) and IL12B rs41292470 (5.36 [1.51–19.0]). In vitro production capacity of interleukin-10 and interferon-γ was influenced by these polymorphisms, and significantly lower proinflammatory cytokine concentrations were measured in serum from patients with persistent fungemia.
Conclusions. Polymorphisms in IL10 and IL12B that result in low production of proinflammatory cytokines are associated with persistent fungemia in candidemia patients. This provides insights for future targeted management strategies for patients with Candida bloodstream infections.
Extremely low birth weight (ELBW) infants with candiduria are at substantial risk for death or neurodevelopmental impairment. Therefore, identification of candiduria should prompt a systemic evaluation for disseminated Candida infection and initiation of treatment in all ELBW infants.
Background. Candidiasis carries a significant risk of death or neurodevelopmental impairment (NDI) in extremely low birth weight infants (ELBW; <1000 g). We sought to determine the impact of candiduria in ELBW preterm infants.
Methods. Our study was a secondary analysis of the Neonatal Research Network study Early Diagnosis of Nosocomial Candidiasis. Follow-up assessments included Bayley Scales of Infant Development examinations at 18–22 months of corrected age. Risk factors were compared between groups using exact tests and general linear modeling. Death, NDI, and death or NDI were compared using generalized linear mixed modeling.
Results. Of 1515 infants enrolled, 34 (2.2%) had candiduria only. Candida was isolated from blood only (69 of 1515 [4.6%]), cerebrospinal fluid (CSF) only (2 of 1515 [0.1%]), other sterile site only (not urine, blood, or CSF; 4 of 1515 [0.3%]), or multiple sources (28 of 1515 [2%]). Eleven infants had the same Candida species isolated in blood and urine within 3 days; 3 (27%) had a positive urine culture result first. Most urine isolates were Candida albicans (21 of 34 [62%]) or Candida parapsilosis (7 of 34 [29%]). Rate of death or NDI was greater among those with candiduria (50%) than among those with suspected but not proven infection (32%; odds ratio, 2.5 [95% confidence interval, 1.2–5.3]) after adjustment. No difference in death and death or NDI was noted between infants with candiduria and those with candidemia.
Conclusions. These findings provide compelling evidence that ELBW infants with candiduria are at substantial risk of death or NDI. Candiduria in ELBW preterm infants should prompt a systemic evaluation (blood, CSF, and abdominal ultrasound) for disseminated Candida infection and warrants treatment.
To improve communication during daily rounds using sequential interventions.
Prospective cohort study
Multidisciplinary pediatric intensive care unit in a university hospital.
The multidisciplinary rounding team in the pediatric intensive care unit, including attending physicians, physician trainees, and nurses.
Daily rounds on 736 patients were observed over a nine month period. Sequential interventions were timed 8–12 weeks apart: (1) Implementing a new resident daily progress note format, (2) creating a performance improvement `dashboard,' and (3) documenting patients' daily goals on bedside whiteboards.
Measurements and Main Results
Following all interventions, team agreement with the attending physician's stated daily goals increased from 56.9% to 82.7% (p < 0.0001). Mean agreement increased for each provider category: 65.2% to 88.8% for fellows (p < 0.0001), 55.0% to 83.8% for residents (p < 0.0001), and 54.1% to 77.4% for nurses (p < 0.0001). In addition, significant improvements were noted in provider behaviors following interventions. Barriers to communication (bedside nurse multitasking during rounds, interruptions during patient presentations, and group disassociation) were reduced, and the use of communication facilitators (review of the prior day's goals, inclusion of bedside nurse input, and order read back) increased. The percentage of providers reporting being `very satisfied' or `satisfied' with rounds increased from 42.6% to 78.3%, (p < 0.0001).
Shared agreement of patients' daily goals among key healthcare providers can be increased through process-oriented interventions. Improved agreement will potentially lead to improved quality of patient care and reduced medical errors.
Teaching Rounds; Communication; Safety; Health Care Quality Assurance; Interdisciplinary Health Team; Intensive Care Units/ Organization & Administration
Background. Candidemia is an important cause of morbidity and mortality in critically ill patients or patients undergoing invasive treatments. Dectin-1 is the main β-glucan receptor, and patients with a complete deficiency of either dectin-1 or its adaptor molecule CARD9 display persistent mucosal infections with Candida albicans. The role of genetic variation of DECTIN-1 and CARD9 genes on the susceptibility to candidemia is unknown.
Methods. We assessed whether genetic variation in the genes encoding dectin-1 and CARD9 influence the susceptibility to candidemia and/or the clinical course of the infection in a large cohort of American and Dutch candidemia patients (n = 331) and noninfected matched controls (n = 351). Furthermore, functional studies have been performed to assess the effect of the DECTIN-1 and CARD9 genetic variants on cytokine production in vitro and in vivo in the infected patients.
Results. No significant association between the single-nucleotide polymorphisms DECTIN-1 Y238X and CARD9 S12N and the prevalence of candidemia was found, despite the association of the DECTIN-1 238X allele with impaired in vitro and in vivo cytokine production.
Conclusions. Whereas the dectin-1/CARD9 signaling pathway is nonredundant in mucosal immunity to C. albicans, a partial deficiency of β-glucan recognition has a minor impact on susceptibility to candidemia.
Suspected or complicated intra-abdominal infections are common in young infants and lead to significant morbidity and mortality. Meropenem is a broad-spectrum antimicrobial agent with excellent activity against pathogens associated with intra-abdominal infections in this population. The purpose of this study was to determine the pharmacokinetics (PK) of meropenem in young infants as a basis for optimizing dosing and minimizing adverse events.
Premature and term infants <91 days of age hospitalized in 24 neonatal intensive care units were studied. Limited PK sampling was performed following single and multiple doses of meropenem 20–30 mg/kg of body weight every 8–12 hours based on postnatal and gestational age at birth. Population and individual patient (Bayesian) PK parameters were estimated using NONMEM®.
Two hundred infants were enrolled and received study drug. One hundred eighty-eight infants with 780 plasma meropenem concentrations were analyzed. Their median (range) gestational age at birth and postnatal age at PK evaluation were 28 (23–40) weeks and 21 (1–92) days, respectively. In the final PK model, meropenem clearance (CL) was strongly associated with serum creatinine (SCR) and postmenstrual age (PMA) (CL [L/h/kg] = 0.12*[(0.5/SCR)**0.27]*[(PMA/32.7)**1.46]). Meropenem concentrations remained >4 μg/mL for 50% of the dose interval and >2 μg/mL for 75% of the dose interval in 96% and 92% of patients, respectively. The estimated penetration of meropenem into the cerebrospinal fluid was 70% (5–148).
Meropenem dosing strategies based on postnatal and gestational age achieved therapeutic drug exposure in almost all infants.
enterocolitis; necrotizing; infant; premature; cerebrospinal fluid
Pharmacokinetic (PK) studies in preterm infants are rarely conducted due to the research challenges posed by this population. To overcome these challenges, minimal-risk methods such as scavenged sampling can be used to evaluate the PK of commonly used drugs in this population. We evaluated the population PK of metronidazole using targeted sparse sampling and scavenged samples from infants that were ≤32 weeks of gestational age at birth and <120 postnatal days. A 5-center study was performed. A population PK model using nonlinear mixed-effect modeling (NONMEM) was developed. Covariate effects were evaluated based on estimated precision and clinical significance. Using the individual Bayesian PK estimates from the final population PK model and the dosing regimen used for each subject, the proportion of subjects achieving the therapeutic target of trough concentrations >8 mg/liter was calculated. Monte Carlo simulations were performed to evaluate the adequacy of different dosing recommendations per gestational age group. Thirty-two preterm infants were enrolled: the median (range) gestational age at birth was 27 (22 to 32) weeks, postnatal age was 41 (0 to 97) days, postmenstrual age (PMA) was 32 (24 to 43) weeks, and weight was 1,495 (678 to 3,850) g. The final PK data set contained 116 samples; 104/116 (90%) were scavenged from discarded clinical specimens. Metronidazole population PK was best described by a 1-compartment model. The population mean clearance (CL; liter/h) was determined as 0.0397 × (weight/1.5) × (PMA/32)2.49 using a volume of distribution (V) (liter) of 1.07 × (weight/1.5). The relative standard errors around parameter estimates ranged between 11% and 30%. On average, metronidazole concentrations in scavenged samples were 30% lower than those measured in scheduled blood draws. The majority of infants (>70%) met predefined pharmacodynamic efficacy targets. A new, simplified, postmenstrual-age-based dosing regimen is recommended for this population. Minimal-risk methods such as scavenged PK sampling provided meaningful information related to development of metronidazole PK models and dosing recommendations.
Neonatal candidiasis is serious and often fatal. Blood culture, the standard for diagnosis, has a sensitivity of 50% or less, and isolate speciation and susceptibility takes several days. This review explores recent advances in Candida detection using various diagnostic strategies.
Handoff communication is a point of vulnerability when valuable patient information can be inaccurate or omitted. In 2005 we implemented a protocol to improve the handoff process for children from the operating room to the intensive care unit after cardiac surgery. We performed a cross-sectional study of the present process to understand how users adapt a communication intervention over time. 29 handoff events were observed. Individuals required for the handoff were present at 97% of events. Content items averaged a 53% reporting rate. Some clinical information not specified in the protocol demonstrated a higher reporting rate, such as echocardiogram results (68%) and vascular access (79%). A mean of 2.3 environmental distractions per minute of communication were noted. Participant-directed adjustments in content reporting suggest that a facilitator in process improvement is user-centered innovation. Future handoff communication interventions should reduce nonessential distractions and incorporate a discussion of the anticipated patient course.
handoff; safety; communication; pediatric intensive care units; congenital heart defects; postoperative care
Necrotizing enterocolitis is associated with high morbidity and mortality among infants admitted for intensive care. The factors associated with mortality and catastrophic presentation remain poorly understood.
To describe the factors associated with mortality in infants with necrotizing enterocolitis and to quantify the degree to which catastrophic presentation contributes to mortality in infants with necrotizing enterocolitis.
We performed a retrospective review of the Pediatrix's Clinical Data Warehouse (1997-2009) to compare the demographic, therapeutic and outcome characteristics of infants who survived NEC versus those who died. Associations were tested by bivariate and multivariate analysis.
In a total cohort of 560,227 infants, there were 2661 cases (17%) of surgically treated and 6460 (42%) of medically treated necrotizing enterocolitis; 1505 (16.5%) died. In multivariate analysis, the factors associated with death (P<0.01 in analysis) were lower estimated gestational age, lower birth weight, a need for assisted ventilation on the day of diagnosis of NEC, a need for vasopressors at the time of diagnosis, and Black race. Patients who received only ampicillin and gentamicin on the day of diagnosis were less likely to die.
Two thirds of NEC deaths occurred quickly (<7 days from diagnosis), with a median time of death of one day from time of diagnosis. Infants who died within 7 days of diagnosis had a higher birth weight, more often required vasopressors and more often were treated with high frequency ventilation at the time of diagnosis compared to patients who died at 7 or more days. Although mortality decreased with increasing gestational age, the proportion of deaths that occur within 7 days was relatively consistent (65-75 percent of the patients who died) across all gestational ages.
Mortality among infants who have necrotizing enterocolitis remains high and infants who die of necrotizing enterocolitis commonly (66%) die quickly. Most of the factors associated with mortality are related to immaturity, low birth weight and severity of illness.
Compare the rates of medical closure of the PDA and complications (renal dysfunction, necrotizing enterocolitis, spontaneous intestinal perforation, and intraventricular hemorrhage) between infants treated with indomethacin and ibuprofen.
A retrospective comparative cohort study of infants treated with indomethacin or ibuprofen for symptomatic patent ductus arteriosus at Duke University Medical Center between November 2005 and November 2007.
We identified 65 infants that received indomethacin and 57 that received ibuprofen. The rate of survival without surgical ductal ligation was 62% (40/65) in the indomethacin group and 58% (33/57) in the ibuprofen group, P=0.71. The rate of the composite of complications (death, necrotizing enterocolitis, or intestinal perforation) was 40% (26/65) in the indomethacin group and 32% (18/57) in the ibuprofen group, P=0.35. There was no significant difference between groups in elevation of serum creatinine during treatment.
In clinical practice, ibuprofen appears to be as effective as indomethacin for closure of patent ductus arteriosus with similar complication rates. The decision to use one agent over the other should be based on dose schedule preference and the currently published clinical trials until more safety and effectiveness data are available.
Ibuprofen; Indomethacin; Patent Ductus Arteriosus; Neonates; Nonsteroidal antiinflammatory drug
Coagulase-negative staphylococci (CoNS) are the most commonly isolated pathogens in the neonatal intensive care unit (NICU). CoNS infections are associated with increased morbidity including neurodevelopmental impairment.
Describe the epidemiology of CoNS infections in the NICU. Determine mortality among infants with definite, probable, or possible CoNS infections.
We performed a retrospective cohort study of all blood, urine, and cerebrospinal fluid cultures from infants <121 postnatal days.
248 NICUs managed by the Pediatrix Medical Group from 1997 to 2009.
We identified 16,629 infants with 17,624 episodes of CoNS infection: 1734 (10%) definite, 3093 (17%) probable, and 12,797 (73%) possible infections. Infants with lower gestational age and birth weight had a higher incidence of CoNS infection. Controlling for gestational age, birth weight, and 5-minute Apgar score, infants with definite, probable, or possible CoNS infection had lower mortality—OR=0.74 (95% confidence interval; 0.61, 0.89), OR= 0.68 (0.59, 0.79), and OR=0.69 (0.63, 0.76)—compared to infants with negative cultures (P<0.001). No significant difference in overall mortality was found in infants with definite CoNS infection compared to those with probable or possible CoNS infection—OR=0.93 (0.75, 1.16) and OR=0.85 (0.70, 1.03), respectively.
CoNS infection was strongly related to lower gestational age and birth weight. Infants with clinical sepsis and culture-positive CoNS infection had lower mortality rates than infants with clinical sepsis and negative blood culture results. No difference in mortality between infants diagnosed with definite, probable, or possible CoNS infection was observed.
nosocomial infection; infant; prematurity; Staphylococcus
Rationale: Benefits of identifying risk factors for bronchopulmonary dysplasia in extremely premature infants include providing prognostic information, identifying infants likely to benefit from preventive strategies, and stratifying infants for clinical trial enrollment.
Objectives: To identify risk factors for bronchopulmonary dysplasia, and the competing outcome of death, by postnatal day; to identify which risk factors improve prediction; and to develop a Web-based estimator using readily available clinical information to predict risk of bronchopulmonary dysplasia or death.
Methods: We assessed infants of 23–30 weeks' gestation born in 17 centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network and enrolled in the Neonatal Research Network Benchmarking Trial from 2000–2004.
Measurements and Main Results: Bronchopulmonary dysplasia was defined as a categorical variable (none, mild, moderate, or severe). We developed and validated models for bronchopulmonary dysplasia risk at six postnatal ages using gestational age, birth weight, race and ethnicity, sex, respiratory support, and FiO2, and examined the models using a C statistic (area under the curve). A total of 3,636 infants were eligible for this study. Prediction improved with advancing postnatal age, increasing from a C statistic of 0.793 on Day 1 to a maximum of 0.854 on Day 28. On Postnatal Days 1 and 3, gestational age best improved outcome prediction; on Postnatal Days 7, 14, 21, and 28, type of respiratory support did so. A Web-based model providing predicted estimates for bronchopulmonary dysplasia by postnatal day is available at https://neonatal.rti.org.
Conclusions: The probability of bronchopulmonary dysplasia in extremely premature infants can be determined accurately using a limited amount of readily available clinical information.
bronchopulmonary dysplasia; prematurity; low-birth-weight infant
Methicillin-resistant Staphylococcus aureus (MRSA) infections are increasing in neonatal intensive care units. We determined the economic impact of isolating and cohorting MRSA colonized neonates on total hospital cost at a 49 bed, level III-IV Neonatal Intensive Care Unit.
MRSA; newborn; length of stay
Many clinical trials, including those in pediatric populations, use a placebo arm for medical conditions for which there are readily available therapeutic interventions. Several short-term efficacy trials of antihypertensive medications performed in response to Food and Drug Administration-issued written requests have used a placebo arm; whether the use of a placebo arm is safe in children with hypertension is unknown. We sought to define the rates of adverse events in 10 short-term antihypertensive trials in order to determine whether these trials resulted in increased risk to pediatric patients receiving placebo. We combined patient-level data from 10 antihypertensive efficacy trials performed in pediatric patients that were submitted to the Food and Drug Administration from 1998–2005. We determined the number and type of all adverse events reported during the placebo-controlled portion of the clinical trials and compared these numbers between the patients who received placebo and those who received active drug. Among the 1707 children in the 10 studies, we observed no differences in the rates of adverse events reported between the patients who received placebo and those who received active drug. Only 5 patients suffered a serious adverse event during the trials; none were thought by the investigators to be related to study drug, and only 1 occurred in a patient receiving placebo. Short-term antihypertensive trials in carefully selected populations of hypertensive children can be safely accomplished with the use of a placebo-control arm.
pediatric drug therapy; hypertension; placebo-controlled clinical trials; adverse events; medical ethics
The Food and Drug Administration (FDA) Modernization Act provided for an additional 6-month period of marketing exclusivity to companies that perform pediatric drug trials in response to an FDA-issued written request. Because many safety concerns cannot be detected until after the introduction of a product to a larger and more diverse market, the Best Pharmaceuticals for Children Act required the FDA to report to the Pediatric Advisory Committee (PAC) on adverse events occurring during the 1-year period after granting pediatric exclusivity. We sought to describe the PAC’s recommendations made in response to safety reviews informed by data from the FDA’s Adverse Event Reporting System in 67 drugs granted exclusivity.
Patients and Methods
PAC meetings and data presented by the FDA for all drugs were reviewed from June 2003 through April 2007. We divided the drugs into 2 groups: those that were returned to routine adverse event monitoring and those that had specific PAC recommendations.
Forty-four (65.7%) drugs were returned to routine monitoring for adverse events. The PAC, sometimes working with other advisory committees, recommended label changes for 12 (17.9%) drugs, continued monitoring for 10 (14.9%), production of MedGuides for 9 (13.4%), and an update on label changes resulting from discussions with the sponsor for 1 (1.5%) drug. Some drugs had more than 1 action. Several of the adverse events revealed during this process were rare and life-threatening.
Safety monitoring during the early post-marketing period is crucial to detect rare, serious, or pediatric-specific adverse events. Fortunately, the majority of drugs given exclusivity had no adverse events of a frequency or severity that prevented a return to routine adverse event monitoring.
pediatric drug safety; Pediatric Advisory Committee; adverse event reporting; drug labeling
candidiasis; fluconazole; infant; neonate; pharmacology
The impact of age and weight on outcomes following the Fontan operation is unclear. Previous analyses have suggested that lower weight-for-age z-score is an important predictor of poor outcome in patients undergoing bidirectional Glenn. We evaluated variation in age, weight, and weight-for-age z-score at Fontan across institutions, and the impact of these variables on post-operative morbidity and mortality.
Patients in the Society of Thoracic Surgeons Congenital Heart Surgery Database undergoing the Fontan operation (2000–2009) were included. Center variation in age, weight, and weight-for-age z-score were described. Multivariable analysis was performed to evaluate the impact of age, weight, and weight-for-age z-score on in-hospital mortality, Fontan failure (combined in-hospital mortality and Fontan takedown/revision), post-operative length of stay, and complications, adjusting for other patient and center factors.
A total of 2747 patients (68 centers) were included: 61% male; 45% right dominant lesions (38% left dominant, 17% undifferentiated). An extracardiac conduit Fontan (vs. lateral tunnel) was performed in 63%; 65% were fenestrated. Median age and weight at Fontan operation and proportion with weight-for-age z-score <−2 varied across centers ranging from 1.7–4.8 yrs, 10.5–16.1 kg, and 0%–30%, respectively. In multivariable analysis, age and weight were not significantly associated with outcome. Weight-for-age z-score <−2 was associated with increased in-hospital mortality (OR 2.73, 95%CI 1.09–6.86), Fontan failure (OR 2.59, 95%CI 1.24–5.40), and longer length of stay (+1.2 days, 95%CI 0.1–2.4).
Weight-for-age z-score <−2 is associated with significant morbidity and mortality following the Fontan operation independent of other patient and center characteristics.
Congenital Heart Disease; Outcomes
Variable approaches to the care of infants with congenital diaphragmatic hernia (CDH) by multiple providers may contribute to inconsistent care. Our institution developed a comprehensive evidence-based protocol to standardize the management of CDH infants. This report reviews patient outcomes prior to and after implementation of the protocol.
Retrospective chart review of CDH infants managed with individualized care (Pre-protocol group, January 1997–December 2001, n=22) or on the protocol (Protocol group, January 2002–July 2009, n=47). Survival and other categorical variables were compared by chi square analysis and continuous variables were compared using one-sided ANOVA analysis with significance defined as p<0.05.
Survival to discharge was significantly greater in the Protocol group (40/47 (85%)) than the Pre-protocol group (12/22 (52%) p=.006) although mean gestational age, mean birth weight, and expected survival were not statistically different between the two groups. The use of supportive therapies, including high frequency jet ventilation, inhaled nitric oxide, and extracorporeal life support was similar between groups as well.
Since implementation of a management protocol for infants with CDH, survival has improved significantly compared with expected survival and pre-protocol controls. Reduction in the variability of care through use of an evidence-based protocol use may improve the survival of CDH infants.
Congenital diaphragmatic hernia; variability; evidence-based care guidelines; protocolized care
We investigated the performance of AST to platelet ratio index (APRI) as a non-invasive marker of fibrosis and cirrhosis in children with chronic viral hepatitis. All patients 0–20 years old with chronic hepatitis B or C seen at a tertiary medical center from 1992–2008 were identified. 36 patients were evaluated with 48 biopsy results. The areas under the ROC curve were 0.71 for fibrosis and 0.52 for cirrhosis. When examining subgroups, the APRI performed better in older patients and in those with vertically transmitted HCV. Further research into APRI and other non-invasive markers of fibrosis in children with chronic viral hepatitis is warranted.
hepatitis B; hepatitis C; APRI; non-invasive markers; fibrosis
Invasive Candida infections are a leading cause of mortality and morbidity in neonatal intensive care units (NICUs). Micafungin is a promising therapeutic option for treatment of invasive fungal infections in infants given its safety profile in older children and adults. Understanding micafungin safety in infants is particularly important because antifungals are most often used in premature infants with multiple underlying medical conditions in a critical care setting.
This article reviews the literature evaluating the safety profile of micafungin in infants and offers recommendations for optimal dosing for treatment of invasive candidiasis in the NICU setting. The review was performed using a Medline search in September 2010 for related articles from 1990 to present with the Mesh related terms ‘micafungin’ and ‘safety’ in combination with the free words ‘antifungal’, ‘candidiasis’, ‘drug toxicity’, ‘infant, premature’, and ‘infant, newborn’.
Despite the limitations of the existing literature, we believe micafungin dosing of 10 mg/kg/day for all term and preterm infants is a viable treatment option in the NICU setting for management of invasive candidiasis. Although the number of infants for whom safety data are reported is small, higher doses of micafungin appear safe and well-tolerated in this population.
adverse effects; drug toxicity; micafungin; premature infants