Air stacking (AS) and mechanical insufflation–exsufflation (MI-E) aim to increase cough efficacy by augmenting inspiratory lung volumes in patients with neuromuscular diseases (NMDs). We studied the ...short-term effect of AS and MI-E on lung function. We prospectively included NMD patients familiar with daily AS or MI-E use. Studied outcomes were forced vital capacity (FVC), forced expiratory volume in one second (FEV1), and peak expiratory flow (PEF) prior to, immediately after, and up to 2 h after treatment. Paired sample T-test and Wilcoxon signed-rank test was used. Sixty-seven patients participated. We observed increased FVC and FEV1 immediately after AS with a mean difference of respectively 0.090 L (95% CI 0.045; 0.135, p < .001) and 0.073 L (95% CI 0.017; 0.128, p = .012). Increased FVC immediately after MI-E (mean difference 0.059 L (95% CI 0.010; 0.109, p = .021) persisted 1 hour (mean difference 0.079 L (95% CI 0.034; 0.125, p = .003). The effect of treatment was more pronounced in patients diagnosed with Spinal Muscular Atrophy, compared to patients with Duchenne muscular dystrophy. AS and MI-E improved FVC immediately after treatment, which persisted 1 h after MI-E. There is insufficient evidence that short-lasting increases in FVC would explain the possible beneficial effect of AS and MI-E.
Progressive lung function decline, resulting in respiratory failure, is an important complication of spinal muscular atrophy (SMA). The ability to predict the need for mechanical ventilation is ...important. We assessed longitudinal patterns of lung function prior to chronic respiratory failure in a national cohort of treatment-naïve children and adults with SMA, hypothesizing an accelerated decline prior to chronic respiratory failure.
We included treatment-naïve SMA patients participating in a prospective national cohort study if they required mechanical ventilation because of chronic respiratory failure and if lung function test results were available from the years prior to initiation of ventilation. We analyzed Forced Vital Capacity (FVC), Forced Expiratory Volume in 1 s (FEV
), Peak Expiratory Flow (PEF) and Maximum Expiratory Pressure (PE
). We studied the longitudinal course using linear mixed-effects models. We compared patients who electively started mechanical ventilation compared to patients who could not be weaned after acute respiratory failure.
We analyzed 385 lung function tests from 38 patients with SMA types 1c-3a. At initiation of ventilation median age was 18.8 years (IQR: 13.2-30.1) and median standardized FVC, FEV
and PEF were 28.8% (95% CI: 23.5; 34.2), 28.8% (95% CI: 24.0; 33.7) and 30.0% (95% CI: 23.4; 36.7), with an average annual decline of 1.75% (95% CI: 0.86; 2.66), 1.72% (95% CI: 1.04; 2.40) and 1.65% (95% CI: 0.71; 2.59), respectively. Our data did not support the hypothesis of an accelerated decline prior to initiation of mechanical ventilation. Median PE
was 35.3 cmH
O (95% CI: 29.4; 41.2) at initiation of mechanical ventilation and relatively stable in the years preceding ventilation. Median FVC, FEV
PEF and PE
were lower in patients who electively started mechanical ventilation (p < 0.001).
Patterns of lung function decline cannot predict impending respiratory failure: SMA is characterized by a gradual decline of lung function. We found no evidence for an accelerated deterioration. In addition, PE
remains low and stable in the years preceding initiation of ventilation. Patients who electively started mechanical ventilation had more restrictive lung function at initiation of ventilation, compared to patients who could not be weaned after surgery or a respiratory tract infection.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
OBJECTIVE:Acute kidney injury requiring continuous renal replacement therapy is a serious treatment-related complication in pediatric cancer and hematopoietic stem cell transplant patients. The ...purpose of this study was to assess epidemiology and outcome of these patients requiring continuous renal replacement therapy in the PICU.
DESIGN:A nationwide, multicenter, retrospective, observational study.
SETTING:Eight PICUs of a tertiary care hospitals in the Netherlands.
PATIENTS:Pediatric cancer and hematopoietic stem cell transplant patients (cancer and noncancer) who received continuous renal replacement therapy from January 2006 to July 2017 in the Netherlands.
INTERVENTIONS:None.
MEASUREMENT AND MAIN RESULTS:Of 1,927 PICU admissions of pediatric cancer and hematopoietic stem cell transplant patients, 68 of 70 evaluable patients who received continuous renal replacement therapy were included. Raw PICU mortality was 11.2% (216/1,972 admissions). PICU mortality of patients requiring continuous renal replacement therapy was 54.4% (37/68 patients). Fluid overload (odds ratio, 1.08; 95% CI, 1.01–1.17) and need for inotropic support (odds ratio, 6.53; 95% CI, 1.86–23.08) at the start of continuous renal replacement therapy were associated with PICU mortality. Serum creatinine levels increased above 150% of baseline 3 days before the start of continuous renal replacement therapy. Urine production did not reach the critical limit of oliguria. In contrast, body weight (fluid overload) increased already 5 days prior to continuous renal replacement therapy initiation.
CONCLUSIONS:PICU mortality of pediatric cancer and hematopoietic stem cell transplant patients requiring continuous renal replacement therapy is sadly high. Fluid overload at the initiation of continuous renal replacement therapy is the most important and earliest predictor of PICU mortality. Our results suggest that the most commonly used criteria of acute kidney injury, that is, serum creatinine and urine production, are not useful as a trigger to initiate continuous renal replacement therapy. This highlights the urgent need for prospective studies to generate recommendations for effective therapeutic interventions at an early phase in this specific patient population.
IntroductionHospitalised paediatric oncology patients are at risk to develop acute complications. Early identification of clinical deterioration enabling adequate escalation of care remains ...challenging. Various Paediatric Early Warning Systems (PEWSs) have been evaluated, also in paediatric oncology patients but mostly in retrospective or case–control study designs. This study protocol encompasses the first prospective cohort with the aim of evaluating the predictive performance of a modified Bedside PEWS score for non-elective paediatric intensive care unit (PICU) admission or cardiopulmonary resuscitation in hospitalised paediatric oncology patients.Methods and analysisA prospective cohort study will be conducted at the 80-bed Dutch paediatric oncology hospital, where all national paediatric oncology care has been centralised, directly connected to a shared 22-bed PICU. All patients between 1 February 2019 and 1 February 2021 admitted to the inpatient nursing wards, aged 0–18 years, with an International Classification of Diseases for Oncology (ICD-O) diagnosis of paediatric malignancy will be eligible. A Cox proportional hazard regression model will be used to estimate the association between the modified Bedside PEWS and time to non-elective PICU transfer or cardiopulmonary arrest. Predictive performance (discrimination and calibration) will be assessed internally using resampling validation. To account for multiple occurrences of the event of interest within each patient, the unit of study is a single uninterrupted ward admission (a clinical episode).Ethics and disseminationThe study protocol has been approved by the institutional ethical review board of our hospital (MEC protocol number 16-572/C). We adapted our enrolment procedure to General Data Protection Regulation compliance. Results will be disseminated at scientific conferences, regional educational sessions and publication in peer-reviewed journals.Trial registration numberNetherlands Trial Registry (NL8957).
OBJECTIVES:A growing body of evidence suggests that age affects the main pathophysiologic mechanisms of the acute respiratory distress syndrome. This may imply the need for developing age-tailored ...therapies for acute respiratory distress syndrome. However, underlying molecular mechanisms governing age-related susceptibility first need to be unraveled. In a rat model of acute lung injury, we investigated whether age affects the balance between the two key enzymes of the pulmonary renin-angiotensin system, angiotensin-converting enzyme, and angiotensin-converting enzyme 2. We hypothesized that aging shifts the balance toward the lung injury–promoting angiotensin-converting enzyme, which may form an explanation for the differences in severity of lung injury between different age groups.
DESIGN:Prospective, randomized controlled animal study.
SETTING:University medical research laboratory.
SUBJECTS:Infant (15 ± 2 d), juvenile (37 ± 2 d), adult (4 ± 0.2 mo), and elderly (19.5 ± 0.5 mo) male RCCHan Wistar rats.
INTERVENTIONS:Lung injury was induced by intratracheal administration of lipopolysaccharide (5 mg/kg) and 4 hours of mechanical ventilation (15 mL/kg).
MEASUREMENTS AND MAIN RESULTS:In lipopolysaccharide-exposed and mechanical ventilated rats, angiotensin-converting enzyme activity in bronchoalveolar lavage fluid increased 3.2-fold in elderly when compared with infants. No changes in bronchoalveolar lavage fluid angiotensin-converting enzyme 2 activity were found. In addition, membrane-bound angiotensin-converting enzyme activity decreased. Together with the presence of angiotensin-converting enzyme-sheddase ADAM9 (a disintegrin and metalloproteinase domain–containing protein 9) and an age-dependent increase in tumor necrosis factor-α, an activator of ADAM9, these results indicate increased shedding of angiotensin-converting enzyme in the alveolar compartment, thereby shifting the balance toward the injurious pathway. This imbalance was associated with an increased inflammatory mediator response and more lung injury (wet-to-dry ratio and histology) in elderly rats.
CONCLUSIONS:Increasing age is associated with an imbalance of the pulmonary renin-angiotensin system, which correlates with aggravated inflammation and more lung injury. These changes might form the ground for new therapeutic strategies in terms of dosing and effectiveness of renin-angiotensin system–modulating agents for treatment of acute respiratory distress syndrome.
Pediatric oncology patients have increased risk for critical illness; outcomes are well described in high-income countries (HICs); however, data is limited for low- and middle-income countries ...(LMICs).BACKGROUNDPediatric oncology patients have increased risk for critical illness; outcomes are well described in high-income countries (HICs); however, data is limited for low- and middle-income countries (LMICs).We systematically searched PubMed, EMBASE, Web of Science, CINAHL and Global Health databases for articles in 6 languages describing mortality in children with cancer admitted to intensive care units (ICUs) in LMICs. Two investigators independently assessed eligibility, data quality, and extracted data. We pooled ICU mortality estimates using random effect models.METHODSWe systematically searched PubMed, EMBASE, Web of Science, CINAHL and Global Health databases for articles in 6 languages describing mortality in children with cancer admitted to intensive care units (ICUs) in LMICs. Two investigators independently assessed eligibility, data quality, and extracted data. We pooled ICU mortality estimates using random effect models.Of 3,641 studies identified, 22 studies were included, covering 4,803 ICU admissions. Overall pooled mortality was 30.3% 95% Confidence-interval (CI) 21.7-40.6%. Mechanical ventilation odds ratio (OR) 12.2, 95%CI:6.2-24.0, p-value<0.001 and vasoactive infusions OR 6.3 95%CI:3.3-11.9, p-value<0.001 were associated with ICU mortality.RESULTSOf 3,641 studies identified, 22 studies were included, covering 4,803 ICU admissions. Overall pooled mortality was 30.3% 95% Confidence-interval (CI) 21.7-40.6%. Mechanical ventilation odds ratio (OR) 12.2, 95%CI:6.2-24.0, p-value<0.001 and vasoactive infusions OR 6.3 95%CI:3.3-11.9, p-value<0.001 were associated with ICU mortality.ICU mortality among pediatric oncology patients in LMICs is similar to that in HICs, however, this review likely underestimates true mortality due to underrepresentation of studies from low-income countries.CONCLUSIONSICU mortality among pediatric oncology patients in LMICs is similar to that in HICs, however, this review likely underestimates true mortality due to underrepresentation of studies from low-income countries.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Spinal muscular atrophy (SMA) is a relatively common autosomal recessive neuromuscular disorder, characterised by progressive degeneration of spinal cord and bulbar motor neurons. It is caused by ...survival motor neuron (SMN) protein deficiency, due to homozygous loss of function of the
SMN1
gene. Due to the effects of genetic modifiers, SMA displays a broad range in severity. The current clinical classification system distinguishes four types, based on age at onset and acquired motor milestones,
i.e.
infantile onset without achieving the ability to sit (type 1), childhood onset with the ability to sit but not to walk (type 2), childhood onset with the ability to walk for at least a short period of time (type 3) and adult onset with mild symptoms (type 4) 1, 2. Disease course is progressive, irrespective of type 3 and patients with SMA type 1, 2 and 3 are at high or moderate risk of developing respiratory insufficiency, which may necessitate initiating mechanical ventilation 4, 5.
Lower ranges of carbon dioxide levels are normal in non-ventilated SMA patients. Physicians should be aware of pending respiratory insufficiency if carbon dioxide levels increase to normal levels in patients with pre-existing low carbon dioxide levels
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Brain microstructural maturation progresses rapidly in the third trimester of gestation and first weeks of life, but typical microstructural development may be influenced by the presence of critical ...congenital heart disease (CHD).
The aim of this study was to investigate the pattern of white matter (WM) microstructural development in neonates with different types of critical CHD. The secondary aim was to examine whether there is an association between WM microstructural maturity and neonatal ischemic brain injury.
For this prospective, longitudinal cohort study, 74 term born neonates underwent diffusion tensor imaging (DTI) before (N = 56) and after (N = 71) cardiac surgery performed <30 days of life for transposition of the great arteries (TGA), single ventricle physiology with aortic arch obstruction (SVP-AO), left- (LVOTO) or right ventricle outflow tract obstruction (RVOTO). Microstructural integrity was investigated by fractional anisotropy (FA) and by mean diffusivity (MD) in 16 white matter (WM) structures in three WM regions with correction for postmenstrual age. Ischemic brain injury was defined as moderate-severe white matter injury or stroke.
Before cardiac surgery, the posterior parts of the corona radiata and internal capsule showed significantly higher FA and lower MD compared to the anterior parts. Centrally-located WM structures demonstrated higher FA compared to peripherally-located structures. Neonates with TGA had higher FA in projection-, association- and commissural WM before surgery, when compared to other CHD groups. Neonates with LVOTO showed lower preoperative MD in these regions, and neonates with SVP-AO higher MD. Differences in FA/MD between CHD groups were most clear in centrally located WM structures. Between CHD groups, no differences in postoperative FA/MD or in change from pre- to postoperative FA/MD were seen. Neonatal ischemic brain injury was not associated with pre- or postoperative FA/MD.
Collectively, these findings revealed brain microstructural WM development to follow the same organized pattern in critical CHD as reported in healthy and preterm neonates, from posterior-to-anterior and central-to-peripheral. Neonates with TGA and LVOTO showed the most mature WM microstructure before surgery and SVP-AO the least mature. Degree of WM microstructural immaturity was not associated with ischemic brain injury.
•Preoperative white matter integrity related to critical CHD type.•Largest difference across CHD types in most mature white matter structures.•Pattern of white matter development not related to critical CHD type.•White matter maturity not related to higher risk neonatal ischemic brain injury.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Aim
To assess the relationship between neonatal brain development and injury with early motor outcomes in infants with critical congenital heart disease (CCHD).
Method
Neonatal brain magnetic ...resonance imaging was performed after open‐heart surgery with cardiopulmonary bypass. Cortical grey matter (CGM), unmyelinated white matter, and cerebellar volumes, as well as white matter motor tract fractional anisotropy and mean diffusivity were assessed. White matter injury (WMI) and arterial ischaemic stroke (AIS) with corticospinal tract (CST) involvement were scored. Associations with motor outcomes at 3, 9, and 18 months were corrected for repeated cardiac surgery.
Results
Fifty‐one infants (31 males, 20 females) were included prospectively. Median age at neonatal surgery and postoperative brain magnetic resonance imaging was 7 days (interquartile range IQR 5–11d) and 15 days (IQR 12–21d) respectively. Smaller CGM and cerebellar volumes were associated with lower fine motor scores at 9 months (CGM regression coefficient=0.51, 95% confidence interval CI=0.15–0.86; cerebellum regression coefficient=3.08, 95% CI=1.07–5.09) and 18 months (cerebellum regression coefficient=2.08, 95% CI=0.47–5.12). The fractional anisotropy and mean diffusivity of white matter motor tracts were not related with motor scores. WMI was related to lower gross motor scores at 9 months (mean difference −0.8SD, 95% CI=−1.5 to −0.2). AIS with CST involvement increased the risk of gross motor problems and muscle tone abnormalities. Cerebral palsy (n=3) was preceded by severe ischaemic brain injury.
Interpretation
Neonatal brain development and injury are associated with fewer favourable early motor outcomes in infants with CCHD.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
BACKGROUND:Advanced age is associated with an increased susceptibility and mortality of the acute respiratory distress syndrome. This may be due to the progressive changes in innate immune responses ...and intrinsic properties of the lung that occur during the process of aging. Therefore, this study assesses the association between maturation and aging and pulmonary responses to injury in animal models of lung injury.
METHODS:A systematic search was conducted in PubMed, EMBASE (up to June 2014) and in the references of relevant articles to identify the studies using in vivo models of lung injury caused by an acute pulmonary insult, in which at least two age groups were compared. Because methodological diversity precluded combining these studies in a quantitative meta-analysis, data are presented based on the qualitative comparison with the adult group.
RESULTS:Of the 2,840 identified studies, 51 were included in this review. Most studies showed that, in response to a pulmonary insult, increasing age is associated with more pulmonary inflammation, edema, alveolar damage, and higher mortality. In addition, results indicate the existence of age-dependent changes in key components of the intracellular signaling pathways involved in the inflammatory response.
CONCLUSIONS:Increasing age seems to be correlated with exaggerated pulmonary responses to injury, ultimately leading to more severe lung injury. Pulmonary inflammation seems relatively suppressed in infants/juveniles, whereas in the middle aged/elderly, the inflammatory response seems delayed but aggravated. This implies that investigators and clinicians need to use caution about extrapolating results from adolescent or youngadult animals to pediatric or elderly patients in clinical practice.
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