Trends in Childhood Oncology Admissions to ICUs in Australia and New Zealand.

OBJECTIVES: There are few robust, national-level reports of contemporary trends in pediatric oncology admissions, resource use, and mortality. We aimed to describe national-level data on trends in intensive care admissions, interventions, and survival for children with cancer. DESIGN: Cohort study using a binational pediatric intensive care registry. SETTING: Australia and New Zealand. PATIENTS: Patients younger than 16 years, admitted to an ICU in Australia or New Zealand with an oncology diagnosis between January 1, 2003, and December 31, 2018. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We examined trends in oncology admissions, ICU interventions, and both crude and risk-adjusted patient-level mortality. Eight thousand four hundred ninety admissions were identified for 5,747 patients, accounting for 5.8% of PICU admissions. Absolute and population-indexed oncology admissions increased from 2003 to 2018, and median length of stay increased from 23.2 hours (interquartile range [IQR], 16.8-62 hr) to 38.8 hours (IQR, 20.9-81.1 hr) ( p < 0.001). Three hundred fifty-seven of 5,747 patients died (6.2%). There was a 45% reduction in risk-adjusted ICU mortality, which reduced from 3.3% (95% CI, 2.1-4.4) in 2003-2004 to 1.8% (95% CI, 1.1-2.5%) in 2017-2018 ( p trend = 0.02). The greatest reduction in mortality seen in hematological cancers and in nonelective admissions. Mechanical ventilation rates were unchanged from 2003 to 2018, while the use of high-flow nasal prong oxygen increased (incidence rate ratio, 2.43; 95% CI, 1.61-3.67 per 2 yr). CONCLUSIONS: In Australian and New Zealand PICUs, pediatric oncology admissions are increasing steadily and such admissions are staying longer, representing a considerable proportion of ICU activity. The mortality of children with cancer who are admitted to ICU is low and falling.

Gestational Age and Risk of Mortality in Term-Born Critically Ill Neonates Admitted to PICUs in Australia and New Zealand.

OBJECTIVES: Gestational age at birth is declining, probably because more deliveries are being induced. Gestational age is an important modifiable risk factor for neonatal mortality and morbidity. We aimed to investigate the association between gestational age and mortality in hospital for term-born neonates (≥ 37 wk') admitted to PICUs in Australia and New Zealand. DESIGN: Observational multicenter cohort study. SETTING: PICUs in Australia and New Zealand. PATIENTS: Term-born neonates (≥ 37 wk) admitted to PICUs. INTERVENTIONS: None MEASUREMENTS AND MAIN RESULTS:: We studied 5,073 infants born with a gestational age greater than or equal to 37 weeks and were less than 28 days old when admitted to a PICU in Australia or New Zealand between 2007 and 2016. The association between gestational age and mortality was estimated using a multivariable logistic regression model, adjusting for age, sex, indigenous status, Pediatric Index of Mortality version 2, and site. The median gestational age was 39.1 weeks (interquartile range, 38.2-40 wk) and mortality in hospital was 6.6%. Risk of mortality declined log-linearly with gestational age. The adjusted analysis showed a 20% (95% CI, 11-28%) relative reduction in mortality for each extra week of gestation beyond 37 weeks. The effect of gestation was stronger among those who received extracorporeal life support: each extra week of gestation was associated with a 44% (95% CI, 25-57%) relative reduction in mortality. Longer gestation was also associated with reduced length of stay in hospital: each week increase in gestation, the average length of stay decreased by 4% (95% CI, 2-6%). CONCLUSIONS: Among neonates born at "term" who are admitted to a PICU, increasing gestational age at birth is associated with a substantial reduction in the risk of dying in hospital. The maturational influence on outcome was more strongly noted in the sickest neonates, such as those requiring extracorporeal life support. This information is important in view of the increasing proportion of planned births in both high- and low-/middle-income countries.

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.

Identifying Children at Risk of Malignant Bordetella pertussis Infection.

OBJECTIVE: To identify factors associated with malignant pertussis. DESIGN: A retrospective case notes review from January 2003 to August 2013. Area under the receiver-operator characteristic curve was used to determine how well vital sign and white cell characteristics within 48 hours of hospital presentation identified children with malignant pertussis. SETTING: The national children's hospital in Auckland, New Zealand. PATIENTS: One hundred fifty-two children with pertussis. MEASUREMENTS AND MAIN RESULTS: There were 152 children with confirmed pertussis identified, including 11 children with malignant pertussis. The area under the receiver-operator characteristic curve was 0.88 (95% CI, 0.78-0.97) for maximum heart rate. The optimal cut-point was 180 beats/min, which predicted malignant pertussis with a sensitivity of 73% and a specificity of 91%. The area under the receiver-operator characteristic curve was 0.92 (95% CI, 0.81-1.0) for absolute neutrophil count, 0.85 (95% CI, 0.71-0.99) for total WBC count, 0.80 (95% CI, 0.63-0.96) for neutrophil-to-lymphocyte ratio, and 0.77 (95% CI, 0.58-0.92) for absolute lymphocyte count. All children with malignant pertussis had one or more of heart rate greater than 180 beats/min, total WBC count greater than 25 × 10/L, and neutrophil-to-lymphocyte ratio greater than 1.0 with an area under the receiver-operator characteristic curve of 0.96 (95% CI, 0.91-1.0) for a multivariate model that included these three variables. CONCLUSIONS: Clinical predictors of malignant pertussis are identifiable within 48 hours of hospital presentation. Early recognition of children at risk of malignant pertussis may facilitate early referral to a PICU for advanced life support and selection for trials of investigational therapies.

Burden and Outcomes of Severe Pertussis Infection in Critically Ill Infants.

OBJECTIVES: Despite World Health Organization endorsed immunization schedules, Bordetella pertussis continues to cause severe infections, predominantly in infants. There is a lack of data on the frequency and outcome of severe pertussis infections in infants requiring ICU admission. We aimed to describe admission rates, severity, mortality, and costs of pertussis infections in critically ill infants. DESIGN: Binational observational multicenter study. SETTING: Ten PICUs and 19 general ICUs in Australia and New Zealand contributing to the Australian and New Zealand Paediatric Intensive Care Registry. PATIENTS: Infants below 1 year of age, requiring intensive care due to pertussis infection in Australia and New Zealand between 2002 and 2014. MEASUREMENTS AND MAIN RESULTS: During the study period, 416 of 42,958 (1.0%) infants admitted to the ICU were diagnosed with pertussis. The estimated population-based ICU admission rate due to pertussis ranged from 2.1/100,000 infants to 18.6/100,000 infants. Admission rates were the highest among infants less than 60 days old (p < 0.0001). Two hundred six infants (49.5%) required mechanical ventilation, including 20 (4.8%) treated with high-frequency oscillatory ventilation, 16 (3.8%) with inhaled nitric oxide, and 7 (1.7%) with extracorporeal membrane oxygenation. Twenty of the 416 children (4.8%) died. The need for mechanical ventilation, high-frequency oscillatory ventilation, nitric oxide, and extracorporeal membrane oxygenation were significantly associated with mortality (p < 0.01). Direct severe pertussis-related hospitalization costs were in excess of USD$1,000,000 per year. CONCLUSIONS: Pertussis continues to cause significant morbidity and mortality in infants, in particular during the first months of life. Improved strategies are required to reduce the significant healthcare costs and disease burden of this vaccine-preventable disease.

Bacteroides fragilis concealed in an infant with Escherichia coli meningitis.

Anaerobic meningitis in infants is rare, therefore a high index of clinical suspicion is essential as routine methods for processing cerebrospinal fluid (CSF) do not detect anaerobes and specific antimicrobial therapy is required. We present an infant with Escherichia coli meningitis where treatment-resistance developed in association with culture negative purulent CSF. These features should have alerted us to the presence of anaerobes, prompting a search for the causes of polymicrobial meningitis in infants.

Serum biomarkers in severe paediatric traumatic brain injury-a narrative review.

Severe traumatic brain injury continues to present complex management and prediction challenges for the clinician. While there is some evidence that better systems of care can improve outcome, multiple multi-centre randomised controlled trials of specific therapies have consistently failed to show benefit. In addition, clinicians are challenged in attempting to accurately predict which children will recover well and which children will have severe and persisting neurocognitive deficits. Traumatic brain injury is vastly heterogeneous and so it is not surprising that one therapy or approach, when applied to a mixed cohort of children in a clinical trial setting, has yielded disappointing results. Children with severe traumatic brain injury have vastly different brain injury pathologies of widely varying severity, in any number of anatomical locations at what may be disparate stages of brain development. This heterogeneity may also explain why clinicians are unable to accurately predict outcome. Biomarkers are objective molecular signatures of injury that are released following traumatic brain injury and may represent a way of unifying the heterogeneity of traumatic brain injury into a single biosignature. Biomarkers hold promise to diagnose brain injury severity, guide intervention selection for clinical trials, or provide vital prognostic information so that early intervention and rehabilitation can be planned much earlier in the course of a child's recovery. Serum S100B and serum NSE levels show promise as a diagnostic tool with biomarker levels significantly higher in children with severe TBI including children with inflicted and non-inflicted head injury. Serum S100B and serum NSE also show promise as a predictor of neurodevelopmental outcome. The role of biomarkers in traumatic brain injury is an evolving field with the potential for clinical application within the next few years.

Isolated congenital mitral valve regurgitation presenting in the first year of life.

AIM: Isolated congenital mitral regurgitation is rare and, when presenting in infancy, reflects severity of the malformation. The natural history is often fatal, and management during the first year of life remains a therapeutic challenge. These infants are poorly understood largely because of an absence of reporting in the medical literature and limited experience in each institution. We reviewed our own experience in order to add to the understanding of this condition. METHODS: A retrospective review was performed on seven infants with significant isolated congenital mitral regurgitation. An associated patent ductus arteriosus was present in two. Mean age at referral was 17.7 weeks (1 day to 47 weeks) and mean weight was 6.8 kg (3.7-12.5 kg). RESULTS: Two infants were managed conservatively, and one underwent surgical ligation of a patent ductus arteriosus. Following spontaneous and surgical duct closure, no further intervention was required in two infants. The remaining four infants underwent three valve repairs and three valve replacements. The in-hospital mortality was 29%, occurring in those under 1 year of age undergoing emergency valve surgery. Two reoperations followed mitral valve repair in the first year of life. No significant complications or late deaths occurred. CONCLUSIONS: Our experience suggests closure of a patent ductus arteriosus should be undertaken prior to mitral valve surgery. There may be a poorer prognosis in those under one year of age requiring emergency mitral valve surgery. Those who can be managed conservatively or undergo mitral valve surgery as an elective procedure tend to have a better outcome.

Transnasal Humidified Rapid Insufflation Ventilatory Exchange in children requiring emergent intubation (Kids THRIVE): a protocol for a randomised controlled trial.

INTRODUCTION: Emergency intubation of children with abnormal respiratory or cardiac physiology is a high-risk procedure and associated with a high incidence of adverse events including hypoxemia. Successful emergency intubation is dependent on inter-related patient and operator factors. Preoxygenation has been used to maximise oxygen reserves in the patient and to prolong the safe apnoeic time during the intubation phase. Transnasal Humidified Rapid Insufflation Ventilatory Exchange (THRIVE) prolongs the safe apnoeic window for a safe intubation during elective intubation. We designed a clinical trial to test the hypothesis that THRIVE reduces the frequency of adverse and hypoxemic events during emergency intubation in children and to test the hypothesis that this treatment is cost-effective compared with standard care. METHODS AND ANALYSIS: The Kids THRIVE trial is a multicentre randomised controlled trial performed in participating emergency departments and paediatric intensive care units. 960 infants and children aged 0-16 years requiring emergency intubation for all reasons will be enrolled and allocated to THRIVE or control in a 1:1 allocation with stratification by site, age (<1, 1-7 and >7 years) and operator (junior and senior). Children allocated to THRIVE will receive weight appropriate transnasal flow rates with 100% oxygen, whereas children in the control arm will not receive any transnasal oxygen insufflation. The primary outcomes are defined as follows: (1) hypoxemic event during the intubation phase defined as SpO2 <90% (patient-dependent variable) and (2) first intubation attempt success without hypoxemia (operator-dependent variable). Analyses will be conducted on an intention-to-treat basis. ETHICS AND DISSEMINATION: Ethics approval for the protocol and consent process has been obtained (HREC/16/QRCH/81). The trial has been actively recruiting since May 2017. The study findings will be submitted for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: ACTRN12617000147381.

Fluid bolus therapy in critically ill children: a survey of practice among paediatric intensive care doctors in Australia and New Zealand.

OBJECTIVE: Fluid bolus therapy (FBT) is a widely used intervention in paediatric critical illness. The aim of this study was to describe the attitudes and practices towards FBT of paediatric intensive care doctors in Australia and New Zealand. DESIGN: An internet-based survey of paediatric intensive care doctors in Australia and New Zealand between 7 and 30 November 2016. SETTING: Paediatric intensive care units with greater than 400 admissions annually. PARTICIPANTS: Paediatric intensive care specialists and junior medical staff. MAIN OUTCOME MEASURES: Preferences for FBT and markers of fluid responsiveness. RESULTS: There were 106/175 respondents (61%); 0.9% saline and 4% albumin are used frequently or almost always by 86% and 57% of respondents respectively. The preferred volume and duration were 10 mL/kg in less than 10 minutes. The highest rated markers of fluid responsiveness were heart rate and blood pressure - rated as "good" or "very good" by 75% and 58% of respondents respectively. Central venous saturations and serum lactate were the highest rated biochemical markers. The most frequently expected magnitude of change for heart rate and blood pressure was 6-15% by 89% and 76% of respondents respectively. The preferred fluid composition for sepsis, trauma, traumatic brain injury and acute lung injury was 0.9% saline, and 4% albumin for post-operative cardiac surgery. CONCLUSIONS: Paediatric intensive care doctors prefer 0.9% saline and 4% albumin for FBT. Heart rate and blood pressure are the most preferred markers to assess fluid responsiveness. Preferences for FBT in specific conditions exist.

Amlodipine-induced bilateral upper extremity edema.

OBJECTIVE: To report a case of bilateral upper extremity edema associated with amlodipine use in a child. CASE SUMMARY: A previously well and normotensive 6-year-old girl presented with a generalized vasculitis of unknown origin and severe hypertension. Large vessels predominantly affecting the neck, chest, and abdomen were found to be involved, resulting in abnormal arterial circulation and significant blood pressure differences between the upper and lower extremities. Multiple antihypertensive agents were initially required to control blood pressure. She was stabilized and discharged on amlodipine 10 mg each evening, atenolol 50 mg/day, and warfarin. Three days later she was noted to have facial and bilateral upper extremity pitting edema. Laboratory and radiologic assessments for possible etiologies were negative. Discontinuation of amlodipine resulted in resolution of edema. DISCUSSION: As of June 2007, there had been no cases of bilateral upper extremity edema associated with amlodipine use reported in the English literature. Adverse effects of amlodipine, a widely used antihypertensive, have been well reported. These include flushing, headache, and peripheral edema. Lower limb edema is the most common, while periocular and perioral edema have occurred less frequently. Anasarca edema has been described only once in the English literature. According to the Naranjo probability scale, amlodipine was a probable cause of bilateral upper extremity edema in this child. CONCLUSIONS: Bilateral upper extremity edema has been associated with amlodipine use in a child with an abnormal arterial circulation. The edema resolved upon discontinuation of the drug.

Increasing Incidence of Life-threatening Pertussis: A Retrospective Cohort Study in New Zealand.

BACKGROUND: Pertussis immunization programs aim to prevent severe infant disease. We investigated temporal trends in infant pertussis deaths and pediatric intensive care unit (PICU) admissions and associations of changes in disease detection and vaccines used with death and PICU admission rates. METHODS: Using national data from New Zealand (NZ), we described infant pertussis deaths and PICU admissions from 1991 to 2013, over which time national immunization coverage at 2 years of age increased from <80% to 92%. In NZ, pertussis became a notifiable disease with polymerase chain reaction (PCR) diagnosis available in 1997 and acellular replaced whole-cell vaccine in 2000. We used Poisson regression to model temporal trends and compared rates in time intervals using rate ratios (RRs) with 95% confidence intervals (CIs). RESULTS: There were 10 pertussis deaths and 159 infant PICU admissions with pertussis from 1991 to 2013. The annual number of infant pertussis PICU admissions increased from 1991 to 2013 (P = 0.02) but the number of pertussis deaths did not (P = 0.09). The risk of PICU admission during infancy with pertussis was increased in the notification/PCR versus the non-notification/PCR era (RR: 1.12; 95% CI: 1.02-1.19) and when acellular replaced whole-cell vaccine (RR: 1.19; 95% CI: 1.06-1.31). Median Pediatric Index of Mortality scores during 2001-2013 were lower than during 1991-1999 (P < 0.001). CONCLUSIONS: Infant PICU pertussis admission rates have increased in NZ despite improvements in immunization coverage. Higher rates have occurred since pertussis notification/PCR became available and since acellular replaced whole-cell vaccine. The severity of disease in infants admitted to PICU with pertussis has decreased in recent years.

Hospital costs of Bordetella pertussis in New Zealand children.

AIM: To estimate hospitalisation costs for children with pertussis in New Zealand. METHOD: All children less than 16 years of age and hospitalised with pertussis between 01/01/2003 and 31/12/2013 were identified from the National Minimum Data Set and the National Paediatric Intensive Care Unit database. The cost of hospital care was estimated by multiplying the diagnosis-related group cost-weight by the national price and inflating to 2013/2014 values. RESULTS: There were 1,456 children with pertussis admitted to hospital including 65 admissions to the paediatric intensive care unit. Infants (<1 year) accounted for 78% of hospital admissions, 98% of paediatric intensive care admissions and 87% of hospitalisation costs. The total inflation-adjusted cost of the 11-year cohort was estimated at $8.3 million and the mean cost of hospital ward and paediatric intensive care was $4,242 and $42,016 respectively, per child. The 2011-2013 epidemic accounted for 39% of all hospital admissions and the cost estimated at $4.2 million. Peak annual hospitalisation costs during epidemic years increased from under $800,000 in 2004 and 2009 to over $2 million in 2012. CONCLUSION: Infants with pertussis are more likely than older children to be admitted to hospital and to the paediatric intensive care unit and generate the majority of hospitalisation costs. A revised focus on protecting vulnerable newborns and infants has the potential to both improve health outcomes for infants with pertussis and reduce medical costs.

Deep hypothermic circulatory arrest during the arterial switch operation is associated with reduction in cerebral oxygen extraction but no increase in white matter injury.

OBJECTIVE: Deep hypothermic circulatory arrest may be associated with increased neural injury. We investigated whether short periods of deep hypothermic circulatory arrest are associated with altered neurophysiologic recovery or greater risk of injury. METHODS: Eighteen term infants with transposition of the great arteries undergoing the arterial switch operation were enrolled. Deep hypothermic circulatory arrest was used in 11, and bypass alone in 7. Near-infrared spectroscopy and amplitude-integrated electroencephalography were recorded with standard monitoring during and from 4 to 16 h after surgery. Fractional tissue oxygen extraction was determined from arterial oxygen saturation and venous weighted intracerebral oxygenation. Magnetic resonance imaging was performed before and 5 to 7 days after surgery. RESULTS: There were no significant differences between patients requiring deep hypothermic circulatory arrest (median, 5 min; range, 3-6 min) or cardiopulmonary bypass only at the beginning of surgery. At the end of surgery, amplitude-integrated electroencephalography minimum amplitude was significantly lower in the deep hypothermic circulatory arrest group (P < .05), and fractional tissue oxygen extraction tended to be lower (P = .068). After surgery, deep hypothermic circulatory arrest was associated with significantly higher tissue oxygenation index, lower fractional tissue oxygen extraction, and lower core temperature (P < .05). Magnetic resonance imaging-defined white matter injuries before and after surgery were similar between groups. CONCLUSIONS: In this prospective, observational study, brief deep hypothermic circulatory arrest during arterial switch was associated with reduced cerebral oxygen uptake during recovery, with transient electroencephalographic suppression but no increase in risk of white matter injury.