Helena Frndova

Changes in structure, mechanics, and insulin-like growth factor-related gene expression in the lungs of newborn rats exposed to air or 60% oxygen.

Exposure of neonatal rats to ≥95% O2 for 2 wk, a widely used model of oxidant/antioxidant interactions in neonatal lung injury, results in arrested lung growth without the dysplastic lesions observed in chronic human neonatal lung injury. To determine whether dysplastic lung cell growth would be seen at lesser O2 concentrations, we exposed newborn rats to either 95% O2 for 1 wk followed by 60% O2 for 1 wk, or to 60% O2 for 2 wk. Exposure to 95% O2 for 1 wk profoundly inhibited lung DNA synthesis. Recovery of synthesis did not occur during the 2nd wk in 60% O2, nor were areas of dysplastic growth evident in lung tissue. In contrast, a continuous 2-wk exposure to 60% O2 resulted in a slight increase in lung weight with a significant reduction in lung volume over a range of inflation pressures. Also seen was an overall, but inhomogeneous, reduction in lung cell DNA synthesis. A preliminary analysis of affected cell types suggested that inhibition of DNA synthesis affected endothelial cells more than interstitial cells, whereas DNA synthesis increased in type II pneumocytes. Areas of reduced DNA synthesis were interspersed with patchy areas of parenchymal thickening and active DNA synthesis. These areas of parenchymal thickening, but not other areas, had increased immunoreactive IGF-I and the type I IGF receptor. These data are consistent with a direct effect of O2 on growth factor and growth factor receptor expression in causing dysplastic lung cell growth in chronic neonatal lung injury.

Seizure burden is independently associated with short term outcome in critically ill children

Seizures are common among critically ill children, but their relationship to outcome remains unclear. We sought to quantify the relationship between electrographic seizure burden and short-term neurological outcome, while controlling for diagnosis and illness severity. Furthermore, we sought to determine whether there is a seizure burden threshold above which there is an increased probability of neurological decline. We prospectively evaluated all infants and children admitted to our paediatric and cardiac intensive care units who underwent clinically ordered continuous video-electroencephalography monitoring over a 3-year period. Seizure burden was quantified by calculating the maximum percentage of any hour that was occupied by electrographic seizures. Outcome measures included neurological decline, defined as a worsening Paediatric Cerebral Performance Category score between hospital admission and discharge, and in-hospital mortality. Two hundred and fifty-nine subjects were evaluated (51% male) with a median age of 2.2 years (interquartile range: 0.3 days-9.7 years). The median duration of continuous video-electroencephalography monitoring was 37 h (interquartile range: 21-56 h). Seizures occurred in 93 subjects (36%, 95% confidence interval = 30-42%), with 23 (9%, 95% confidence interval = 5-12%) experiencing status epilepticus. Neurological decline was observed in 174 subjects (67%), who had a mean maximum seizure burden of 15.7% per hour, compared to 1.8% per hour for those without neurological decline (P < 0.0001). Above a maximum seizure burden threshold of 20% per hour (12 min), both the probability and magnitude of neurological decline rose sharply (P < 0.0001) across all diagnostic categories. On multivariable analysis adjusting for diagnosis and illness severity, the odds of neurological decline increased by 1.13 (95% confidence interval = 1.05-1.21, P = 0.0016) for every 1% increase in maximum hourly seizure burden. Seizure burden was not associated with mortality (odds ratio: 1.003, 95% confidence interval: 0.99-1.02, P = 0.613). We conclude that in this cohort of critically ill children, increasing seizure burden was independently associated with a greater probability and magnitude of neurological decline. Our observation that a seizure burden of more than 12 min in a given hour was strongly associated with neurological decline suggests that early antiepileptic drug management is warranted in this population, and identifies this seizure burden threshold as a potential therapeutic target. These findings support the hypothesis that electrographic seizures independently contribute to brain injury and worsen outcome. Our results motivate and inform the design of future studies to determine whether more aggressive seizure treatment can improve outcome.

Lung recruitment and lung volume maintenance: a strategy for improving oxygenation and preventing lung injury during both conventional mechanical ventilation and high-frequency oscillation

Objective: To determine whether using a small tidal volume (5 ml/kg) ventilation following sustained inflation with positive end-expiratory pressure (PEEP) set above the critical closing pressure (CCP) allows oxygenation equally well and induces as little lung damage as high-frequency oscillation following sustained inflation with a continuous distending pressure (CDP) slightly above the CCP of the lung.¶Material and methods: Twelve surfactant-depleted adult New Zealand rabbits were ventilated for 4 h after being randomly assigned to one of two groups: group 1, conventional mechanical ventilation, tidal volume 5 ml/kg, sustained inflation followed by PEEP > CCP; group 2, high-frequency oscillation, sustained inflation followed by CDP > CCP.¶Results: In both groups oxygenation improved substantially after sustained inflation (P < 0.05) and remained stable over 4 h of ventilation without any differences between the groups. Histologically, both groups showed only little airway injury to bronchioles, alveolar ducts, and alveolar airspace, with no difference between the two groups. Myleoperoxidase content in homogenized lung tissue, as a marker of leukocyte infiltration, was equivalent in the two groups.¶Conclusions: We conclude that a volume recruitment strategy during small tidal volume ventilation and maintaining lung volumes above lung closing is as protective as that of high-frequency oscillation at similar lung volumes in this model of lung injury

Remote ischaemic preconditioning protects against cardiopulmonary bypass-induced tissue injury: a preclinical study.

Objectives: To test the hypothesis that remote ischaemic preconditioning (rIPC) reduces injury after cardiopulmonary bypass (CPB). Design: Randomised study with an experimental model of CPB (3 h CPB with 2 h of cardioplegic arrest). Twelve 15 kg pigs were randomly assigned to control or rIPC before CPB and followed up for 6 h. Intervention: rIPC was induced by four 5 min cycles of lower limb ischaemia before CPB. Main outcome measures: Troponin I, glial protein S-100B, lactate concentrations, load-independent indices (conductance catheter) of systolic and diastolic function, and pulmonary resistance and compliance were measured before and for 6 h after CPB. Results: Troponin I increased after CPB in both groups but during reperfusion the rIPC group had lower concentrations than controls (mean area under the curve −57.3 (SEM 7.3) v 89.0 (11.6) ng·h/ml, p  =  0.02). Lactate increased after CPB in both groups but during reperfusion the control group had significantly more prolonged hyperlactataemia (p  =  0.04). S-100B did not differ between groups. Indices of ventricular function did not differ. There was a tendency to improved lung compliance (p  =  0.07), and pulmonary resistance changed less in the rIPC than in the control group during reperfusion (p  =  0.02). Subsequently, peak inspiratory pressure was lower (p  =  0.001). Conclusion: rIPC significantly attenuated clinically relevant markers of myocardial and pulmonary injury after CPB. Transient limb ischaemia as an rIPC stimulus has potentially important clinical applications.

Phenotypic abnormalities in long-term surviving cystic fibrosis mice.

Mouse models for cystic fibrosis (CF) with no CFTR function(Cftr-/-) have the disadvantage that most animals die of intestinal obstruction shortly after weaning. The objective of this research was to extend the lifespan of CF mice and characterize their phenotype. Weanlings were placed on a nutrient liquid diet, and histologic and functional aspects of organs implicated in the disease were subsequently examined. Approximately 90% of Cftr-/- mice survived to 60 d, the majority beyond 100 d. Cftr-/- mice were underweight and had markedly abnormal intestinal histology. The intestinal epithelia did not respond to challenges with agents that raised intracellular cAMP, consistent with the absence of functional CFTR. No lesions or functional abnormalities were evident in the lungs. Liquid-fed Cftr-/- mice were infertile, although some males weaned to a solid diet were fertile before they died. Thus, we have succeeded in using dietary means to prolong the lives ofCftr-/- mice.

Quantifying the volume of documented clinical information in critical illness

OBJECTIVES The purpose of this study is to describe the volume of clinical information documented in critical illness, its relationship to the use of intensive care unit (ICU) technology, and changes over time. METHODS We performed a 6-year retrospective cohort study. Eligible patients were admitted to a university-affiliated pediatric ICU for at least 24 hours during the years 2000 to 2005. For each complete 24-hour period (midnight-midnight) that each patient was admitted to the ICU, we extracted the total number of items of documented clinical information and the use of 5 ICU technologies. For each day of the study, we calculated the total volume of documented information available to inform the daily ward round. A 2-level hierarchical linear model was used to analyze the primary outcome variable. MAIN MEASUREMENTS AND RESULTS There were 5623 admissions and 41202 complete patient-days studied. The median number of items of documented clinical data for each complete 24-hour period was 1348 (interquartile range, 1018-1664; mean, 1341). Significantly, more clinical information was documented about children who were ventilated with conventional ventilation (1483), children on inotropes or vasoactive medications (1685) and high-frequency oscillation (1726), and children receiving extracorporeal membrane oxygenation therapy (2354) or hemodialysis (1889) than children not in these categories (all P < .0001). The number of items documented per patient-day increased by 26% from 1165 in 2000 to 1471 items in 2005 (P < .0001). This finding was independent of ICU technology use. CONCLUSIONS A large and increasing volume of information was documented during the course of critical illness. More information was documented in patients receiving ICU technologies, suggesting that the volume of documented information is a marker of therapeutic intensity. It is also a source of workload and provides opportunity for error. Our findings underscore the importance of effective information management and communication strategies. Additional work is needed to evaluate the implications of current documentation practices for workload and quality of care.

Aerosol delivery of an enhanced helper-dependent adenovirus formulation to rabbit lung using an intratracheal catheter

Poor transduction of the ciliated airway epithelium and inefficient airway delivery of viral vectors are common difficulties encountered in lung gene therapy trials with large animals and humans.

Novel method to quantify loss of heart rate variability in pediatric multiple organ failure.

ObjectiveTo develop a power-law model for measurement of heart rate variability (HRV) and to compare this model with established methods for measuring HRV in a group of children with organ failure (OF). DesignProspective, observational study. SettingPediatric intensive care unit of a tertiary children’s hospital. PatientsA total of 104 measurements were made on 50 patients (median age, 8 months; range, 2 days to 16 yrs) and categorized into three groups according to the number of simultaneous organs failing: 0–1 OF, 2 OF, and ≥3 OF. InterventionsHeart rate was recorded over a 5-min period when patients were hemodynamically stable. The power-law model represents a power function relating frequency distribution to magnitude of effect (in this case, squared deviation from the mean heart rate). Plotting the data on a bi-logarithmic scale produces a regression line for each measurement, described in terms of r2, slope, and x-intercept. Comparison with other HRV measures included two time-domain measures (sd of the normal R-R intervals and the square root of the mean squared differences of successive normal R-R intervals), one frequency-domain method (power spectral analysis), and one nonlinear method (detrended fluctuation analysis). Measurements and ResultsFor the power-law model, patients exhibited a similar r2 of .87 (.09) (mean [sd]) and slope of −1.80 (0.29), regardless of the degree of OF. HRV could thus be described purely in terms of x-intercept, which demonstrated a left shift with increasing OF (p < .001). This was independent of age and heart rate. Loss of HRV with increasing OF was demonstrated by all methods; however, only the power-law model was able to discriminate between each OF group. Using the model, change in HRV in individual patients over successive days often concurred qualitatively with the change in OF status. ConclusionThe power-law model is an appropriate measure of HRV in pediatric patients, being neither age nor heart rate sensitive. Loss of HRV occurs with increasing OF; this effect was better demonstrated by the model compared with other measures of HRV.

Impact of Hypotension and Low Cerebral Perfusion Pressure on Outcomes in Children Treated with Hypothermia Therapy following Severe Traumatic Brain Injury: A post hoc Analysis of the Hypothermia Pediatric Head Injury Trial

Hypotension and low cerebral perfusion pressure are known to be associated with unfavorable outcome in children and adults with traumatic brain injury. Using the database from a previously published, randomized controlled trial of 24 h of hypothermia therapy in children with severe traumatic brain injury, we compared the number of patients with hypotension or low cerebral perfusion pressure between the hypothermia therapy and normothermia groups. We also determined the association between these physiologic insults and unfavorable outcome using regression analysis. There were more patients with episodes of hypotension or low cerebral perfusion pressure in the hypothermia therapy group than in the normothermia group. These physiologic insults were associated with unfavorable outcome in both intervention groups. Hypotension and low cerebral perfusion pressure should be anticipated and prevented in future trials of hypothermia therapy in patients with traumatic brain injury.

Distribution of pulmonary blood flow in the perfluorocarbon-filled lung

Objective: Partial liquid ventilation (PLV) improves gas exchange in animal studies of lung injury. Perfluorocarbons (PFCs) are heavy liquids and are therefore preferentially delivered to the most dependent areas of lung. We hypothesised that improved oxygenation during PLV might be the consequence of a redistribution of pulmonary blood flow away from poorly ventilated, dependent alveoli, leading to improved ventilation/perfusion (V/Q) matching. This study investigated whether partially filling the lung with PFC would result in a redistribution of pulmonary blood flow.¶Design: Prospective experimental study.¶Setting: Hospital research institute laboratory.¶Participants: Six anaesthetised pigs without lung injury.¶Interventions: Animals were anaesthetised and ventilated (gas tidal volume 12 ml/kg, PEEP 5, FIO2 1.0, rate 16). Whilst the pigs were maintained in the supine position, regional pulmonary blood flow was measured during conventional gas ventilation and repeated during PLV. Flow to regions of lung was determined by injection of radioactive microspheres (Co57, Sn113, Sc46). Measurements were performed with ventilation held at end-expiratory pressure and, in two PLV animals only, repeated with ventilation held at peak inspiratory pressure.¶Results: During conventional gas ventilation, blood flow followed a linear distribution with the highest flow to the most dependent lung. In the lung partially filled with PFC a diversion of blood flow away from the most dependent lung was seen (p = 0.007), resulting in a more uniform distribution of flow down the lung (p = 0.006). Linear regression analysis (r2 = 0.75) also confirmed a difference in distribution pattern. On applying an inspiratory hold to the liquid-containing lung, blood flow was redistributed back towards the dependent lung.¶Conclusions: Partially filling the lung with PFC results in a redistribution of pulmonary blood flow away from the dependent region of the lung. During PLV a different blood flow distribution may be seen between inspiration and expiration. The clinical significance of these findings has yet to be determined.