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.

Outcomes of paediatric critical care asthma patients.

AIM: The aim of this study was to characterise patients with asthma admitted to an Australian paediatric intensive care unit (PICU). METHODS: This was a retrospective review of patients with asthma admitted to a university-affiliated, 23-bed, tertiary PICU between January 2000 and December 2011, with a subset of pharmacotherapy and biochemical data from patients admitted between July 2007 and December 2011. RESULTS: A total of 589 admissions (501 patients) with asthma over 12 years constituted 4.4% of all PICU admissions. Three patients died (0.6%). Non-invasive ventilation (NIV) was used in 104 (17.7%) admissions, and 41 (7%) were invasively ventilated. On 12 (2%) occasions, patients received both NIV and invasive ventilation. Over 12 years, there was a significant trend to increased use of NIV, 11-39% (P < 0.0001), and invasive ventilation, 6-14% (P < 0.001). All received steroids and nebulised ß2-agonists. A total of 92% received intravenous (IV) ß2-agonists, 65% of these for less than 12 h. PICU and hospital stay were proportional to the duration of IV ß2-agonist infusion (P < 0.0001). A total of 47.1% received IV magnesium sulphate, increasing from 19 to 75% (P < 0.001). The majority (48%) were transferred directly to PICU from other hospitals. Median PICU stay was 1.04 days (0.72-1.63); hospital stay was 3.16 days (2.29-4.71), and both were unchanged. CONCLUSIONS: Intensive care length of stay (LOS) was unchanged over 12 years. Both invasive and NIV and IV magnesium sulphate use increased. LOS was directly related to the duration of IV ß2-agonist. Asthma patients admitted to PICU typically have a brief stay and have a fairly predictable course. Prospective studies could explore the contribution of IV agents and the role of NIV.

Humidified high-flow nasal cannula oxygen in bronchiolitis reduces need for invasive ventilation but not intensive care admission.

AIM: To describe the changes to paediatric intensive care unit (PICU) admission patterns and ventilation requirements for children with bronchiolitis following the introduction of humidified high-flow nasal cannula oxygen outside the PICU. METHODS: Retrospective study comparing patients <24 months of age with a discharge diagnosis of bronchiolitis admitted to the PICU. A comparison was made between those before humidified high-flow nasal cannula oxygen use (year 2008) to those immediately following the introduction of humidified high-flow nasal cannula oxygen use (year 2011) and those following further consolidation of humidified high-flow nasal cannula oxygen use outside the PICU (year 2013). RESULTS: Humidified high-flow nasal cannula oxygen use up to 1 L/kg/min in the hospital did not reduce PICU admission. Intubation rates were reduced from 22.2% in 2008 to 7.8% in 2013. There was a non-significant trend towards decreased length of stay in the PICU while hospital length of stay showed a significant decrease following the introduction of humidified high-flow nasal cannula oxygen. Age <6 months and respiratory syncytial virus bronchiolitis were associated with an increased chance of failing humidified high-flow nasal cannula oxygen therapy. CONCLUSION: Humidified high-flow nasal cannula oxygen utilised outside of the PICU in our institution for children with bronchiolitis did not reduce admission rates or length of stay to the PICU but was associated with a decreasing need for invasive ventilation and reduced hospital length of stay.

Increased connective tissue growth factor associated with cardiac fibrosis in the mdx mouse model of dystrophic cardiomyopathy.

Cardiomyopathy contributes to morbidity and mortality in Duchenne muscular dystrophy (DMD), a progressive muscle-wasting disorder. A major feature of the hearts of DMD patients and the mdx mouse model of the disease is cardiac fibrosis. Connective tissue growth factor (CTGF) is involved in the fibrotic process in many organs. This study utilized the mdx mouse model to assess the role of CTGF and other extracellular matrix components during the development of fibrosis in the dystrophic heart. Left ventricular function of mdx and control mice at 6, 29 and 43 weeks was measured by echocardiography. Young (6 weeks old) mdx hearts had normal function and histology. At 29 weeks of age, mdx mice developed cardiac fibrosis and increased collagen expression. The onset of fibrosis was associated with increased CTGF transcript and protein expression. Increased intensity of CTGF immunostaining was localized to fibrotic areas in mdx hearts. The upregulation of CTGF was also concurrent with increased expression of tissue inhibitor of matrix metalloproteinases (TIMP-1). These changes persisted in 43 week old mdx hearts and were combined with impaired cardiac function and increased gene expression of transforming growth factor (TGF)-ß1 and matrix metalloproteinases (MMP-2, MMP-9). In summary, an association was observed between cardiac fibrosis and increased CTGF expression in the mdx mouse heart. CTGF may be a key mediator of early and persistent fibrosis in dystrophic cardiomyopathy.

Comparison of human metapneumovirus and respiratory syncytial virus in children admitted to a paediatric intensive care unit.

AIM: To describe the clinical presentation and course of children admitted to the paediatric intensive care unit (PICU) with human metapneumovirus (hMPV) infection, and compare them with children admitted to the PICU with respiratory syncytial virus (RSV) infection. METHODS: hMPV was identified by immunofluorescence in 22 children admitted to the PICU over a 16-month period. The medical records of these children were reviewed retrospectively, and their clinical and laboratory data were compared with 66 children admitted to the PICU with positive tests for RSV over the same period. RESULTS: Children admitted to the PICU with hMPV were significantly older than children with RSV (P= 0.003). Children with hMPV presented more commonly with pneumonia or pneumonitis (29% vs. 16%), and less commonly with bronchiolitis (43% vs. 68%) than RSV (P= 0.13). Invasive ventilation was required in 10 patients (48%) with hMPV, and non-invasive ventilation was required in a further 5 (28%), similar to patients with RSV. Children with hMPV were more likely to have an underlying co-morbidity (P= 0.11). CONCLUSIONS: Children admitted to the PICU with hMPV have a similar disease presentation and severity as children admitted with RSV, including some with extremely severe disease who require additional ventilatory or cardiovascular support. Children with hMPV are likely to be older than those with RSV, and more likely to present with pneumonia and less likely to present with bronchiolitis.

Recombinant activated factor VII in neonatal cardiac surgery.

OBJECTIVES: The aim of this study is to determine whether recombinant activated factor VII (rVIIa) was associated with thrombus formation in neonates undergoing cardiac surgery. METHODS: This is a retrospective study of neonates undergoing surgical repair of congenital cardiac lesions during a 9-year period. RESULTS: In our study, 416 cardiac operations requiring cardiopulmonary bypass (CPB) were performed on 414 neonates. The overall intravascular thrombus (thrombus) frequency for all operations was 45 of 416 (11%). A thrombus developed in 17 of 287 (6%) operations when rVIIa was not given. rVIIa was administered in 129 of 416 (31%) operations. Thrombus formation occurred in 28 of 129 (22%) operations when rVIIa was administered. There was an association between rVIIa use and thrombus formation [odds ratio (OR) 4.4, 95% confidence interval (CI) 2.3-8.4; P < 0.0001]. Patients with thrombus formation had an increased length of stay compared to those without thrombus. Neonates who underwent the Norwood procedures and received rVIIa and developed thrombus were more likely to be supported with extracorporeal membrane oxygenation (ECMO) and had a higher mortality compared to Norwood patients without thrombus. Logistic analysis adjusted for the paediatric index of mortality 2 score, the risk adjustment for congenital heart surgery and the use of ECMO demonstrated a strong association between rVIIa administration and thrombus formation (OR 3.5, 95% CI 1.7-6.9; P = 0.0004). However, there was no effect of the risk adjustment for congenital heart surgery-1 category or the paediatric index of mortality 2 score on thrombus formation. CONCLUSIONS: In neonates who underwent CPB surgery, administration of rVIIa was associated with an increased occurrence of intravascular thrombus formation compared to neonates not given rVIIa. In the Norwood population, thrombus formation was associated with a higher mortality.

Changes in skeletal muscle expression of AQP1 and AQP4 in dystrophinopathy and dysferlinopathy patients.

Transmembrane water transport is mediated by aquaporins (AQPs), of which AQP1 and AQP4 are expressed in skeletal muscle. AQP4 expression is reduced in Duchenne muscular dystrophy (DMD) patients, and is reported to correlate with decreased alpha1-syntrophin and altered osmotic permeability. In this study, we assessed the relationship between AQP1, AQP4, dystrophin and alpha1-syntrophin in dystrophinopathy and dysferlinopathy patients. Muscle biopsies of patients with DMD (n = 8) and limb-girdle muscular dystrophy type 2B (LGMD2B; n = 5) were screened for AQP1 and AQP4 expression by real-time quantitative RT-PCR or Western blot and immunohistochemistry. AQP expression was further analyzed in primary myotubes derived from DMD and LGMD2B patients by cell culture and immunohistochemistry. AQP1 transcript and protein expression was significantly elevated in DMD biopsies, and was localized to the sarcolemma of muscle fibers and endothelia of muscle capillaries. AQP4 was significantly reduced despite normal dystrophin and alpha1-syntrophin in dysferlinopathy patients, while expression of AQP1 was variably upregulated. Expression of AQP1 and AQP4 was normal in patient-derived primary myotubes, suggesting that altered AQPs observed in biopsies are likely secondary to the dystrophic process. Our study shows that AQP4 downregulation can occur in muscular dystrophies with either normal or disrupted expression of dystrophin-associated proteins, and that this might be associated with upregulation of AQP1.

Myocardial water handling and the role of aquaporins.

Cardiac surgery is performed in approximately 770,000 adults and 30,000 children in the United States of America annually. In this review we outline the mechanistic links between post-operative myocardial stunning and the development of myocardial edema. These interrelated processes cause a decline in myocardial performance that account for significant morbidity and mortality after cardiac surgery. Factors leading to myocardial edema include hemodilution, ischemia and reperfusion as well as osmotic gradients arising from pathological change. Several members of the aquaporin family of water transport proteins have been described in the myocardium although their role in the pathogenesis and resolution of cardiac edema is not established. This review examines evidence for the involvement of aquaporins in myocardial water handling during normal and pathological conditions.

Lack of MG53 in human heart precludes utility as a biomarker of myocardial injury or endogenous cardioprotective factor.

AIMS: Mitsugumin-53 (MG53/TRIM72) is an E3-ubiquitin ligase that rapidly accumulates at sites of membrane injury and plays an important role in membrane repair of skeletal and cardiac muscle. MG53 has been implicated in cardiac ischaemia-reperfusion injury, and serum MG53 provides a biomarker of skeletal muscle injury in the mdx mouse model of Duchenne muscular dystrophy. We evaluated the clinical utility of MG53 as a biomarker of myocardial injury. METHODS AND RESULTS: We performed Langendorff ischaemia-reperfusion injury on wild-type and dysferlin-null murine hearts, using dysferlin deficiency to effectively model more severe outcomes from cardiac ischaemia-reperfusion injury. MG53 released into the coronary effluent correlated strongly and significantly (r = 0.79-0.85, P < 0.0001) with functional impairment after ischaemic injury. We initiated a clinical trial in paediatric patients undergoing corrective heart surgery, the first study of MG53 release with myocardial injury in humans. Unexpectedly, we reveal although MG53 is robustly expressed in rat and mouse hearts, MG53 is scant to absent in human, ovine, or porcine hearts. Absence of MG53 in 11 human heart specimens was confirmed using three separate antibodies to MG53, each subject to epitope mapping and confirmed immunospecificity using MG53-deficient muscle cells. CONCLUSION: MG53 is an effective biomarker of myocardial injury and dysfunction in murine hearts. However, MG53 is not expressed in human heart and therefore does not hold utility as a clinical biomarker of myocardial injury. Although cardioprotective roles for endogenous myocardial MG53 cannot be extrapolated from rodents to humans, potential therapeutic application of recombinant MG53 for myocardial membrane injury prevails.

Clinical assessment of cardiac performance in infants and children following cardiac surgery.

OBJECTIVE: To compare clinical assessment of cardiac performance with an invasive method of haemodynamic monitoring. DESIGN AND SETTING: Prospective observational study in a 16-bed tertiary paediatric intensive care unit. PATIENTS AND PARTICIPANTS: Infants and children undergoing cardiopulmonary bypass and surgical repair of congenital heart lesions. INTERVENTIONS: Based on physical examination and routinely available haemodynamic monitoring in the paediatric intensive care unit, medical and nursing staff assessed cardiac index, systemic vascular resistance index and volume status. Clinical assessment was compared with cardiac index, systemic vascular resistance index and global end diastolic volume index, obtained by femoral artery thermodilution. MEASUREMENTS AND RESULTS: A total of 76 clinical estimations of the three parameters were made in 16 infants and children undergoing biventricular repair of congenital heart lesions. Agreement was poor between clinical and invasive methods of determining all three studied parameters of cardiac performance. Cardiac index was significantly underestimated clinically; mean difference was 0.71 l min(-1) m(-2) (95% range of agreement +/-2.7). Clinical estimates of systemic vascular resistance (weighted kappa=0.15) and volume status (weighted kappa=0.04) showed poor levels of agreement with measured values and were overestimated clinically. There was one complication related to a femoral arterial catheter and one device failure. CONCLUSIONS: Routine clinical assessment of parameters of cardiac performance agreed poorly with invasive determinations of these indices. Management decisions based on inaccurate clinical assessments may be detrimental to patients. Invasive haemodynamic monitoring using femoral artery thermodilution warrants cautious further evaluation as there is little agreement with clinical assessment which is presently standard accepted care in this patient population.

Recombinant activated factor VII in paediatric cardiac surgery.

OBJECTIVE: To review the use of recombinant activated factor VII in paediatric cardiac surgery. DESIGN: Retrospective chart review. SETTING: Paediatric intensive care unit in a stand-alone university-affiliated children's hospital. PATIENTS AND PARTICIPANTS: Cardiac surgical patients who received recombinant activated factor VII (rFVIIa, NovoSeven; NovoNordisk, Copenhagen, Denmark) between June 2002 and June 2003 at The Children's Hospital at Westmead. RESULTS: Six children undergoing cardiac surgery received rFVIIa. Recombinant activated factor VII was administered if bleeding was excessive and persisted despite appropriate investigation and attention to haemostasis by surgical and medical staff. An intravenous dose of 180 microg/kg was given and repeated 2 h later. All of the six patients responded well to rFVIIa with achievement of haemostasis. No adverse events were noted. CONCLUSIONS: Recombinant activated factor VII achieved haemostasis in six paediatric cardiac surgical patients. Good outcomes and no adverse events were noted in these children.

Dysfunction induced by ischemia versus edema: does edema matter?

OBJECTIVES: Recovery from pediatric cardiac surgery is affected by ischemia-reperfusion injury, cardiac edema, and in some cases a low cardiac output syndrome. Although association has been made between the development of edema and dysfunction, modeling is confounded by intercurrent injurious stimuli that also cause cardiac edema and dysfunction. We tested whether a true causal relationship exists between edema and cardiac dysfunction. METHODS: We induced either ischemia or edema alone in isolated cardiomyocytes and whole Langendorff-perfused hearts. Function was measured as shortening dynamics and developed pressure, respectively. RESULTS: Ischemic injury impaired function in both cardiomyocytes and whole hearts. Isolated cells showed significant reduction in peak shortening and departure and relaxation velocities. Whole hearts displayed severely reduced developed pressures. Hyposmotic solution forced cardiomyocytes to swell to 7% greater than their normal size. No significant effect on shortening was seen. Similarly, Langendorff-perfused hearts were induced to take on 3% more water than control-perfused hearts and 9% more water than nonperfused hearts. This additional water was associated with mild dysfunction. CONCLUSIONS: We demonstrate the capacity of the heart to tolerate edema greater than that seen in clinical settings without residual effect. Ischemia results in ongoing contractile dysfunction of both isolated cardiomyocytes and whole hearts. We conclude that dysfunction resulting from edema in ex vivo cardiac models is mild and suggest review of the importance given to edema-mediated dysfunction after cardiac surgery.

Myocardial membrane injury in pediatric cardiac surgery: An animal model.

OBJECTIVE: Reduced myocardial performance invariably follows pediatric cardiac surgery and is manifested by a low cardiac output state in its severest form. The role of myocardial membrane proteins in this setting is unknown. Dystrophin and dysferlin are involved in membrane integrity, whereas aquaporins selectively transport water. These proteins were examined in a model of pediatric cardiac surgery, together with a trial of poloxamer 188, which may reduce membrane injury. METHODS: Eight lambs were randomized to saline with or without poloxamer 188. Lambs underwent 2 hours of cardiopulmonary bypass and aortic crossclamping. After a further 9 hours of monitoring, the hearts were assessed for water content, capillary leak, and protein expression. RESULTS: Dystrophin expression was unaffected by ischemia/reperfusion, but dysferlin expression was reduced. Aquaporin 1 protein increased after ischemia/reperfusion. Poloxamer 188 administration was associated with supranormal levels of dystrophin, preservation of dysferlin expression, and normalization of aquaporin 1 expression. Poloxamer 188 was associated with less capillary leak, maintained colloid osmotic pressure, and less hemodilution. Poloxamer 188 was associated with an improved hemodynamic profile (higher blood pressure, higher venous saturation, and lower lactate), although the heart rate tended to be higher. CONCLUSIONS: Changes in protein expression within the myocardial membrane were found in a clinically relevant model of pediatric cardiac surgery. Indicators of reduced performance, such as lower blood pressure and lower oxygen delivery, were lessened in association with the administration of the membrane protecting poloxamer 188. Poloxamer 188 was also associated with potentially beneficial changes in membrane protein expression, reduced capillary leakage, and less hemodilution.

Myocardial ischemia is more important than the effects of cardiopulmonary bypass on myocardial water handling and postoperative dysfunction: a pediatric animal model.

OBJECTIVES: Low cardiac output state is the principal cause of morbidity after surgical intervention for congenital heart disease. Myocardial ischemia-reperfusion injury, apoptosis, capillary leak syndrome, and myocardial edema are associated factors. We established a clinically relevant model to examine relationships between myocardial ischemia, edema, and cardiac dysfunction and to assess the role of the water transport proteins aquaporins. METHODS: Sixteen lambs were studied. Seven were control animals not undergoing cardiopulmonary bypass, and 9 underwent bypass. Six had 90 minutes of aortic crossclamping with blood cardioplegia and moderate hypothermia. The remaining 3 underwent cardiopulmonary bypass without aortic crossclamping. Hemodynamic and biochemical data were recorded, and myocardial edema, apoptotic markers, and aquaporin expression were determined after death. RESULTS: The group undergoing cardiopulmonary bypass with aortic crossclamping had a low cardiac output state, with early postoperative tachycardia, hypotension, increased serum lactate levels, and impaired tissue oxygen delivery (P < .05) compared with the group undergoing cardiopulmonary bypass without aortic crossclamping. The lambs undergoing cardiopulmonary bypass with aortic crossclamping had increased myocardial water (P < .05) compared with those not undergoing cardiopulmonary bypass and a 2-fold increase in aquaporin 1 mRNA expression (P < .05) compared with those not undergoing cardiopulmonary bypass and those undergoing cardiopulmonary bypass without aortic crossclamping. CONCLUSIONS: A temporal association between hemodynamic dysfunction, myocardial edema, and increased aquaporin 1 expression was demonstrated. Cardiopulmonary bypass without ischemia was associated with minimal edema, negligible myocardial dysfunction, and static aquaporin expression. Ischemic reperfusion injury is the main cause of myocardial edema and myocardial dysfunction, but a causal relationship between edema and dysfunction remains to be proved.

Cardiac aquaporin expression in humans, rats, and mice.

Water accumulation in the heart is important in ischemia-reperfusion injury and operations performed by using cardiopulmonary bypass, with cardiac dysfunction associated with myocardial edema being the principal determinant of clinical outcome. As an initial step in determining the role of aquaporin (AQP) water channels in myocardial edema, we have assessed the myocardial expression of AQPs in humans, rats, and mice. RT-PCR revealed expression of AQP-1, -4, -6, -7, -8, and -11 transcripts in the mouse heart. AQP-1, -6, -7, and -11 mRNAs were found in the rat heart as well as low levels of AQP-4 and -9. Human hearts contained AQP-1, -3, -4, -5, -7, -9, -10, and -11 mRNAs. AQP-1 protein expression was confirmed by Western blot analysis in all three species. AQP-4 protein was detected in the mouse heart but not in the rat or human heart. To determine the potential functional consequences of myocardial AQP expression, water permeability was measured in plasma membrane vesicles from myocardial cells of wild-type versus various AQP knockout mice. Water permeability was reduced by AQP-1 knockout but not by AQP-4 or AQP-8 knockout. With the use of a model of isolated rat heart perfusion, it was found that osmotic and ischemic stresses are not associated with changes in AQP-1 or AQP-4 expression. These studies support a possible functional role of AQP-1 in myocardium but indicate that early adaptations to osmotic and ischemic stress do not involve transcriptional or posttranslational AQP-1 regulation.

Levosimendan for low cardiac output: a pediatric experience.

This was a retrospective observational study in a pediatric intensive care unit, in which 19 patients received levosimendan. There were no adverse events attributable to levosimendan and no instances where the clinical condition worsened after administration. Arterial lactate levels decreased significantly following levosimendan administration during cardiopulmonary bypass for anticipated low cardiac output. In those with established low cardiac output, trends toward improved hemodynamics were seen, with heart rate reduction, an increase in mean blood pressure, a reduction in arterial lactate, and reduced conventional inotrope use. Levosimendan was safely used in a small number of pediatric patients with established low cardiac output state who demonstrated improved hemodynamics and tissue perfusion, with a tendency to reduced conventional inotrope usage, and this warrants its evaluation as an inotrope in the pediatric population.