Association Between Centralization and Outcome for Children Admitted to Intensive Care in Australia and New Zealand: A Population-Based Cohort Study.

OBJECTIVES: To describe regional differences and change over time in the degree of centralization of pediatric intensive care in Australia and New Zealand (ANZ) and to compare the characteristics and ICU mortality of children admitted to specialist PICUs and general ICUs (GICUs). DESIGN: A retrospective cohort study using registry data for two epochs of ICU admissions, 2003-2005 and 2016-2018. SETTING: Population-based study in ANZ. PATIENTS: A total of 43,256 admissions of children aged younger than 16 years admitted to an ICU in ANZ were included. Infants aged younger than 28 days without cardiac conditions were excluded. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was risk-adjusted ICU mortality. Logistic regression was used to investigate the association of mortality with the exposure to ICU type, epoch, and their interaction. Compared with children admitted to GICUs, children admitted to PICUs were younger (median 25 vs 47 mo; p < 0.01) and stayed longer in ICU (median 1.6 vs 1.0 d; p < 0.01). For the study overall, 93% of admissions in Australia were to PICUs whereas in New Zealand only 63% of admissions were to PICUs. The adjusted odds of death in epoch 2 relative to epoch 1 decreased (adjusted odds ratio [AOR], 0.50; 95% CI, 0.42-0.59). There was an interaction between unit type and epoch with increased odds of death associated with care in a GICU in epoch 2 (AOR, 1.63; 95% CI, 1.05-2.53 for all admissions; 1.73, CI, 1.002-3.00 for high-risk admissions). CONCLUSIONS: Risk-adjusted mortality of children admitted to specialist PICUs decreased over a study period of 14 years; however, a similar association between time and outcome was not observed in high-risk children admitted to GICUs. The results support the continued use of a centralized model of delivering intensive care for critically ill children.

Factors associated with discharge delay and direct discharge home from paediatric intensive care.

AIM: To examine the patient and hospital admission characteristics associated with direct discharge home from paediatric intensive care. METHODS: This was a single-centre retrospective analysis of all admissions to a tertiary metropolitan general paediatric intensive care unit (ICU) surviving to discharge over a 10-year period between 1 January 2007 and 31 December 2016, divided into two epochs defined by changes in health service structure. Patient and admission characteristics were compared between groups discharged direct to home and discharged to ward across these two epochs. RESULTS: There was a marked increase in the annual rate of direct discharge to home from ICU between the two epochs (3.7-9.5%, P < 0.0001). There was an inverse relationship between monthly ICU activity and rates of direct discharge to home. Patients discharged directly home were significantly more likely to experience delay to discharge (46.4 vs. 30.7%, P < 0.0001), for that delay to exceed 24 h and comprise a greater proportion of total ICU length of stay. Bronchiolitis accounted for an increasing proportion of admissions between epochs (7.0-15.1%) and was over-represented among patients discharged direct to home (up to 18.2%). CONCLUSIONS: The high observed rate of direct discharge home is likely to have resulted from increased delays to discharge and changes to patient admission characteristics, attributable to organisational restructuring and possibly changing approaches to clinical management of bronchiolitis. It is imperative to now consider how we ensure that our systems support the proper use of intensive care resources.

Admission Hyperoxia Is a Risk Factor for Mortality in Pediatric Intensive Care.

OBJECTIVES: To determine whether the association between hyperoxia and increased risk-adjusted mortality in adult intensive care patients is also observed in a pediatric intensive care population. DESIGN: Single-center retrospective analysis of admissions to ICU over a 5-year period commencing January 1, 2012, examining the relationship between PaO2 measured within the first hour of admission and risk-adjusted mortality. Standardized mortality rates were calculated using the Pediatric Index of Mortality-3, and patients were grouped into 50 mm Hg (6.67 kPa) PaO2 bands to assess the relationship between initial PaO2 and risk-adjusted mortality. SETTING: Tertiary PICU with 17 beds and 1,100 annual admissions located in metropolitan Sydney, Australia. PATIENTS: A total of 1,447 patients 0-18 years old with PaO2 recorded at admission to the ICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: There were 5,176 patients admitted to the ICU during the study period and 1,447 (28%) with PaO2 recorded at admission. A U-shaped relationship between raw mortality and admission PaO2 was observed, with lowest mortality (2.3% and 2.6%, respectively) observed in the 101-150 (13.5-20.0 kPa) and 151-200 mm Hg (20.1-26.7 kPa) bands and the highest mortality observed in patients with PaO2 less than 50 mm Hg (6.67 kPa) with mortality of 5.3%, or greater than 350 mm Hg (46.7 kPa) with mortality of 18.2%. Hyperoxia at admission was associated with an increase in risk-adjusted mortality, with polynomial regression indicating a strong correlation between PaO2 band and risk-adjusted outcome (r = 0.845). When included in a multivariate model that included the Pediatric Index of Mortality-3 variables, the odds ratio for hyperoxia (defined as PaO2 > 250 mm Hg [33.3 kPa]) predicting death was 2.66 (p = 0.047). CONCLUSIONS: In this single-center study, hyperoxia at admission to the PICU was highly correlated with increased risk-adjusted mortality. Further investigation of these observations in a large multicenter cohort is warranted.

Venoarterial Extracorporeal Membrane Oxygenation Versus Conventional Therapy in Severe Pediatric Septic Shock.

OBJECTIVES: The role of venoarterial extracorporeal membrane oxygenation in the treatment of severe pediatric septic shock continues to be intensely debated. Our objective was to determine whether the use of venoarterial extracorporeal membrane oxygenation in severe septic shock was associated with altered patient mortality, morbidity, and/or length of ICU and hospital stay when compared with conventional therapy. DESIGN: International multicenter, retrospective cohort study using prospectively collected data of children admitted to intensive care with a diagnosis of severe septic shock between the years 2006 and 2014. SETTING: Tertiary PICUs in Australia, New Zealand, Netherlands, United Kingdom, and United States. PATIENTS: Children greater than 30 days old and less than 18 years old. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 2,452 children with a diagnosis of sepsis or septic shock, 164 patients met the inclusion criteria for severe septic shock. With conventional therapy (n = 120), survival to hospital discharge was 40%. With venoarterial extracorporeal membrane oxygenation (n = 44), survival was 50% (p = 0.25; CI, -0.3 to 0.1). In children who suffered an in-hospital cardiac arrest, survival to hospital discharge was 18% with conventional therapy and 42% with venoarterial extracorporeal membrane oxygenation (Δ = 24%; p = 0.02; CI, 2.5-42%). Survival was significantly higher in patients who received high extracorporeal membrane oxygenation flows of greater than 150 mL/kg/min compared with children who received standard extracorporeal membrane oxygenation flows or no extracorporeal membrane oxygenation (82%, 43%, and 48%; p = 0.03; CI, 0.1-0.7 and p < 0.01; CI, 0.2-0.7, respectively). Lengths of ICU and hospital stay were significantly longer for children who had venoarterial extracorporeal membrane oxygenation. CONCLUSIONS: The use of venoarterial extracorporeal membrane oxygenation in severe pediatric sepsis is not by itself associated with improved survival. However, venoarterial extracorporeal membrane oxygenation significantly reduces mortality after cardiac arrest due to septic shock. Venoarterial extracorporeal membrane oxygenation flows greater than 150 mL/kg/min are associated with almost twice the survival rate of conventional therapy or standard-flow extracorporeal membrane oxygenation.

Early cystic fibrosis lung disease detected by bronchoalveolar lavage and lung clearance index.

RATIONALE: Unrecognized airway infection and inflammation in young children with cystic fibrosis (CF) may lead to irreversible lung disease; therefore early detection and treatment is highly desirable. OBJECTIVES: To determine whether the lung clearance index (LCI) is a sensitive and repeatable noninvasive measure of airway infection and inflammation in newborn-screened children with CF. METHODS: Forty-seven well children with CF (mean age, 1.55 yr) and 25 healthy children (mean age, 1.26 yr) underwent multiple-breath washout testing. LCI within and between-test variability was assessed. Children with CF also had surveillance bronchoalveolar lavage performed. MEASUREMENTS AND MAIN RESULTS: The mean (SD) LCI in healthy children was 6.45 (0.49). The LCI was higher in children with CF (7.21 [0.81]; P < 0.001). The upper limit of normal for the LCI was 7.41. Fifteen (32%) children with CF had an elevated LCI. LCI measurements were repeatable and reproducible. Airway infection was present in 17 (36%) children with CF, including 7 (15%) with Pseudomonas aeruginosa. Polymicrobial growth was associated with worse inflammation. The LCI was higher in children with Pseudomonas (7.92 [1.16]) than in children without Pseudomonas (7.02 [0.56]) (P = 0.038). The LCI correlated with bronchoalveolar lavage IL-8 (R(2) = 0.20, P = 0.004) and neutrophil count (R(2) = 0.21, P = 0.001). An LCI below the upper limit of normality had a high negative predictive value (93%) in excluding Pseudomonas. CONCLUSIONS: The LCI is elevated early in CF, especially in the presence of Pseudomonas and airway inflammation. The LCI is a feasible, repeatable, and sensitive noninvasive marker of lung disease in young children with CF.

Extremes of weight centile are associated with increased risk of mortality in pediatric intensive care.

INTRODUCTION: Although numerous studies have linked extremes of weight with poor outcome in adult intensive care patients, the effect of weight on intensive care outcome has not previously been reported in the pediatric population. The aim of this study was to investigate the relationship between admission weight centile and risk-adjusted mortality in pediatric intensive care patients. METHODS: Data were collected on 6337 consecutively admitted patients over an 8.5 year period in a 15 bed pediatric intensive care unit (ICU) located in a university-affiliated tertiary referral children's hospital. A weight centile variable was entered into a multivariate logistic regression model that included all other pediatric index of mortality (PIM-2) variables, in order to determine whether weight centile was an independent risk factor for mortality. RESULTS: Weight centile was associated with mortality in both univariate and multivariate analysis, with the lowest mortality being associated with weights on the 75th centile and increasing symmetrically around this nadir. A transformed weight centile variable (absolute value of weight centile-75) was independently associated with mortality (odds ratio 1.02, P = 0.000) when entered into a multivariate logistic regression model that included the PIM-2 variables. CONCLUSIONS: In this single-center cohort, weight centile was an independent risk factor for mortality in the ICU, with mortality increasing for patients at either end of the weight spectrum. These observations suggest that the accuracy of mortality prediction algorithms may be improved by inclusion of weight centile in the models. A prospective multicenter study should be undertaken to confirm our findings.

RACHS - ANZ : A Modified Risk Adjustment in Congenital Heart Surgery Model for Outcome Surveillance in Australia and New Zealand.

Background Outcomes for pediatric cardiac surgery are commonly reported from international databases compiled from voluntary data submissions. Surgical outcomes for all children in a country or region are less commonly reported. We aimed to describe the bi-national population-based outcome for children undergoing cardiac surgery in Australia and New Zealand and determine whether the Risk Adjustment for Congenital Heart Surgery ( RACHS ) classification could be used to create a model that accurately predicts in-hospital mortality in this population. Methods and Results The study was conducted in all children's hospitals performing cardiac surgery in Australia and New Zealand between January 2007 and December 2015. The performance of the original RACHS -1 model was assessed and compared with an alternative RACHS - ANZ (Australia and New Zealand) model, developed balancing discrimination with parsimonious variable selection. A total of 14 324 hospital admissions were analyzed. The overall hospital mortality was 2.3%, ranging from 0.5% for RACHS category 1 procedures, to 17.0% for RACHS category 5 or 6 procedures. The original RACHS -1 model was poorly calibrated with death overpredicted (1161 deaths predicted, 289 deaths observed). The RACHS - ANZ model had better performance in this population with excellent discrimination (Az- ROC of 0.830) and acceptable Hosmer and Lemeshow goodness-of-fit ( P=0.216). Conclusions The original RACHS -1 model overpredicts mortality in children undergoing heart surgery in the current era. The RACHS - ANZ model requires only 3 risk variables in addition to the RACHS procedure category, can be applied to a wider range of patients than RACHS -1, and is suitable to use to monitor regional pediatric cardiac surgery outcomes.

After-hours admissions are not associated with increased risk-adjusted mortality in pediatric intensive care.

OBJECTIVE: To examine the influence of time of admission on risk-adjusted mortality and length of stay for nonelective patients admitted to a pediatric intensive care unit (ICU) without 24-h per day in-house intensivist coverage. DESIGN: Data analyzed came from a comprehensive, prospectively collected ICU database. SETTING: A 12-bed pediatric ICU located in a university-affiliated tertiary referral children's hospital. PATIENTS: Subjects consisted of 4,456 consecutive nonelective patients admitted over a 10-year period (1997-2006). INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Patients were categorized according to time of admission to the ICU as either in-hours (0800-1800 Monday-Friday and 0800-1200 on weekends), when an intensivist is present in the ICU, or after-hours (all other times), when intensivists attend only on an as-needed basis. Multivariate logistic regression was used to assess the effect of time of admission on outcome after adjustment for severity of illness using the Paediatric Index of Mortality (PIM). Patients admitted after hours had a lower risk-adjusted mortality than those admitted during normal working hours, with an odds ratio for death of 0.712 (95% confidence interval 0.518-0.980, p = 0.037). Length of stay was also significantly shorter for patients admitted after hours (44.05h vs. 50.0h, p = 0.001). CONCLUSIONS: A lack of in-house intensivist presence is not associated with any increase in mortality or length of stay for patients admitted to our pediatric ICU; on the contrary, after-hours admission in this cohort was associated with a decreased risk-adjusted mortality and a shorter length of stay.

Beware the starboard nasogastric tube.

A mycotic pseudoaneurysm of the thoracic aorta is a rare entity in the pediatric population. It carries a high mortality rate associated with spontaneous rupture. Aortoesophageal fistula is a known complication of a pseudoaneurysm but is also rare in this group. A high index of suspicion is needed to make the diagnosis. This is aided by radiograph and computed tomography. We present such a case in an 11-year-old boy with previously undiagnosed coarctation of the aorta.

Acute lung injury in pediatric intensive care in Australia and New Zealand: a prospective, multicenter, observational study.

OBJECTIVE: Acute lung injury (ALI) is poorly defined in children. The objective of this prospective study was to clarify the incidence, demographics, management strategies, outcome, and mortality predictors of ALI in children in Australia and New Zealand. DESIGN: Multicenter prospective study during a 12-month period. SETTING: Intensive care unit. PATIENTS: All children admitted to intensive care and requiring mechanical ventilation were screened daily for development of ALI based on American-European Consensus Conference guidelines. Identified patients were followed for 28 days or until death or discharge. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: There were 117 cases of ALI during the study period, giving a population incidence of 2.95/100,000 <16 yrs. ALI accounted for 2.2% of pediatric intensive care unit admissions. Mortality was 35% for ALI, and this accounted for 30% of all pediatric intensive care unit deaths during the study period. Significant preadmission risk factors for mortality were chronic disease, older age, and immunosuppression. Predictors of mortality during admission were ventilatory requirements (peak inspiratory pressures, mean airway pressure, positive end-expiratory pressure) and indexes of respiratory severity on day 1 (Pao2/Fio2 ratio and oxygenation index). Higher maximum and median tidal volumes were associated with reduced mortality, even when corrected for severity of lung disease. Development of single and multiple organ failure was significantly associated with mortality. CONCLUSIONS: ALI in children is uncommon but has a high mortality rate. Risk factors for mortality are easily identified. Ventilatory variables and indexes of lung severity were significantly associated with mortality.

Role of head computed tomography in the evaluation of children admitted to the paediatric intensive care unit with new-onset seizure.

OBJECTIVE: The role of neuroimaging in children presenting with new-onset seizure is poorly defined. This study evaluates the incidence of abnormal CT findings in children admitted to the paediatric intensive care unit (PICU) with new-onset seizure and examines potential clinical variables associated with abnormal head CT findings. METHODS: A retrospective analysis of 89 previously asymptomatic children admitted to Sydney Children's Hospital (Sydney, Australia) PICU between November 2005 and September 2009 with new-onset seizure was undertaken. Demographic data, clinical details and head CT findings were abstracted from medical records. The clinical significance and the impact of CT findings on acute management decisions was analysed. Clinical variables associated with abnormal clinically significant CT results were examined. RESULTS: A total of 71/89 patients underwent head CT. Of the children who underwent head CT (n= 71), clinically significant CT results were found in 19.7% of patients and head CT findings resulted in a change in acute management in 7% of patients. Children without fever were more than twice as likely to have a positive CT scan (P= 0.049); however, a substantial proportion (6/45) of febrile children also had abnormal scans. Focal seizures were not predictive of abnormal CT results. There was a significant relationship between abnormal CT and multiple seizures (P < 0.02), and age less than 24 months (P < 0.049). CONCLUSION: In this highly selected group head CT findings are frequently abnormal and might change acute management. Children admitted to the PICU with first presentation of seizure who have multiple seizures and/or are aged <2 years should have immediate CT or MRI scanning.

Effect of Ginkgo biloba extract on oxidative metabolism of valproic acid in hepatic microsomes from donors with the CYP2C9*1/*1 genotype.

We investigated the effect of Ginkgo biloba extracts and some of its individual constituents on the oxidative metabolism of valproic acid (VPA) in hepatic microsomes from donors with the CYP2C9*1/*1 genotype. G. biloba extract decreased 4-ene-VPA, 3-OH-VPA, 4-OH-VPA, and 5-OH-VPA formation with mean (+/- SE) IC50 values of 340 +/- 40 microg/mL, 370 +/- 100 microg/mL, 180 +/- 30 microg/mL, and 210 +/- 20 microg/mL, respectively. This was associated with inhibition of not only CYP2C9*1, but also CYP2A6 and CYP2B6. Bilobalide, ginkgolide A, ginkgolide B, ginkgolide C, ginkgolide J, quercetin-3-O-rutinoside, kaempferol-3-O-rutinoside, and isorhamnetin-3-O-rutinoside were not responsible for the inhibition of VPA metabolism by the extract. When analyzed as the sum of the aglycone and total glycosides present in the extract, quercetin decreased 4-ene-VPA, 4-OH-VPA, and 5-OH-VPA formation by 76%, 51%, and 70%, respectively, kaempferol decreased 4-ene-VPA, 4-OH-VPA, and 5-OH-VPA formation by 65%, 46%, and 49%, respectively, and isorhamnetin decreased 4-ene-VPA, 4-OH-VPA, and 5-OH-VPA formation by 29%, 26%, and 31%, respectively. The 3 aglycones did not affect 3-OH-VPA formation. In summary, G. biloba extract decreased hepatic microsomal formation of 4-ene-VPA, 4-OH-VPA, 5-OH-VPA, and 3-OH-VPA, but the effect was not due to the terpene trilactones or flavonol glycosides investigated in our study.

Inflammation, infection, and pulmonary function in infants and young children with cystic fibrosis.

Our aim was to study the effect of lower airway infection on clinical parameters, pulmonary function tests, and inflammation in clinically stable infants and young children with cystic fibrosis (CF). To accomplish this goal, a prospective cohort of screened CF patients under 4 years of age were studied, using elective anesthesia and intubation for: passive respiratory mechanics (single breath occlusion passive deflation) and lung volumes (nitrogen washout), under neuromuscular blockade; and bronchoalveolar lavage (BAL) of 3 main bronchi for cytology, cytokine interleukin (IL)-8, and quantitative microbiology. There were 22 children studied, with a mean age of 23.2 months (6.7-44 months). A greater relative risk of lower airway pathogens was associated with prior respiratory admission (3.60, 95% confidence interval [CI] 2.87-4.51), history of asthma (1.75, 95% CI 1.52-2.03), and chronic symptoms (1.50, 95% CI 1.23-1.83), especially wheeze (1.88, 95% CI 1.61-2.19). Lower respiratory pathogens (> or = 10 cfu/ml BAL) were found in 14 out of 22, and greater than 10(5) cfu/ml in 8 out of 22 subjects. The level of pathogens in BAL (log10 cfu/ml) explained 78% of the variability in percent neutrophils and 34% of the variability in IL-8 levels. Pathogen level also correlated with pulmonary function tests of specific respiratory system compliance (r -0.49, p = 0.02) and functional residual capacity over total lung capacity (r 0.49, p = 0.03). We conclude that the presence of pathogens in the lower airways correlated with levels of inflammation, respiratory system compliance, and degree of air trapping.

Late-onset and recurrent neonatal Group B streptococcal disease associated with breast-milk transmission.

The purpose of the study was to determine the epidemiological relationships in three unrelated cases of neonatal late-onset Group B streptococcal (GBS) disease and maternal breast-milk infection with GBS. All deliveries were by cesarean section; case 1 was at term, and cases 2 and 3 were at 32- and 33-wk gestation, respectively. Case 1 relates to a mother with clinical mastitis and recurrent GBS infection in a 20-day-old male infant. Following antibiotic therapy and cessation of breast-feeding, the infant recovered without sequelae. Case 2 refers to a mother with clinical mastitis and the occurrence of late-onset GBS disease in 5-wk-old male twins. Despite intervention, one infant died and the second became ill. Following antibiotic therapy and cessation of breast-feeding, the surviving infant recovered without sequelae. Case 3 refers to a mother with sub-clinical mastitis and late-onset GBS infection occurring in a 6-day-old female twin. Following intervention, the infant recovered but suffered a bilateral thalamic infarction resulting in developmental delay and a severe seizure disorder. Following recovery of GBS from an inapparent mastitis and cessation of breast-feeding, the second infant remained well. Blood cultures from all affected infants and maternal breast milk were positive for GBS. Epidemiological relationships between neonatal- and maternal-derived GBS isolates were confirmed by a random amplified polymorphic DNA polymerase chain reaction assay (RAPD-PCR). This study is significant in that it has demonstrated that maternal milk (in cases of either clinical or sub-clinical mastitis) can be a potential source of infection resulting in either late-onset or recurrent neonatal GBS disease.