Pharmacokinetics of S-ketamine during prolonged sedation at the pediatric intensive care unit.

BACKGROUND: S-ketamine is the S(+)-enantiomer of the racemic mixture ketamine, an anesthetic drug providing both sedation and analgesia. In clinical practice, significant interpatient variability in drug effect of S-ketamine is observed during long-term sedation. AIMS: The aim of this study was to evaluate the pharmacokinetic variability of S-ketamine in children aged 0-18 years during long-term sedation. Twenty-five children (median age: 0.42 years, range: 0.02-12.5) received continuous intravenous administrations of 0.3-3.6 mg/kg/h S-ketamine for sedation during mechanical ventilation. Infusion rates were adjusted to the desired level of sedation and analgesia based on the COMFORT-B score and Visual Analog Scale. Blood samples were drawn once daily at random time-points, and at 1 and 4 hours after discontinuation of S-ketamine infusion. Time profiles of plasma concentrations of S-ketamine and active metabolite S-norketamine were analyzed using nonlinear mixed-effects modeling software. Clearance and volume of distribution were allometrically scaled using the ¾ power model. RESULTS: A total of 86 blood samples were collected. A 2-compartment and 1-compartment model adequately described the PK of S-ketamine and S-norketamine, respectively. The typical parameter estimates for clearance and central and peripheral volumes of distribution were: CLS-KETAMINE =112 L/h/70 kg, V1S-KETAMINE =7.7 L/70 kg, V2S-KETAMINE =545L/70 kg, QS-kETAMINE =196 L/h/70 kg, and CLS-NORKETAMINE =53 L/h/70 kg. Interpatient variability of CLS-KETAMINE and CLS-NORKETAMINE was considerable with values of 40% and 104%, respectively, leading to marked variability in steady-state plasma concentrations. CONCLUSION: Substantial interpatient variability in pharmacokinetics in children complicates the development of adequate dosage regimen for continuous sedation.

Incidence and Mortality of Acute Respiratory Distress Syndrome in Children: A Systematic Review and Meta-Analysis.

OBJECTIVES: Our understanding of the acute respiratory distress syndrome in children is limited, and literature is dominated by investigations in adult patients. Recent preclinical studies suggest that the susceptibility to and severity of acute respiratory distress syndrome in children could differ from that in adults. We assessed the incidence and mortality of acute respiratory distress syndrome reported in children in studies published in the last two decades. DATA SOURCES: Medline, Embase, and CINAHL databases were searched up to August 2014. STUDY SELECTION: Articles reporting study data on population- or PICU-based incidence and mortality of acute respiratory distress syndrome in children (> 36 wk gestation and < 18 yr old) were selected. DATA EXTRACTION: Two authors independently collected data and assessed methodological quality and risk of bias of selected studies. Pooled estimates of incidence and mortality were calculated using random-effects models. To explore heterogeneity, influence of study characteristics, including median year of conduct, study location, inclusion and exclusion criteria, and study design and quality, was assessed by meta-regression analysis. DATA SYNTHESIS: Twenty-nine studies reported on incidence and 32 on mortality. Pooled weighted estimate of the population-based and PICU-based incidence of pediatric acute respiratory distress syndrome was 3.5 (95% CI, 2.2-5.7) cases per 100,000 person years and 2.3% (95% CI, 1.9-2.9), respectively. Pooled weighted mortality was 33.7% (95% CI, 28.6-39.7). There were no trends over time, but mortality was significantly associated with study location. CONCLUSIONS: This systematic review and meta-analysis shows a low incidence but a high mortality. Its results also indicate that both incidence and mortality of pediatric acute respiratory distress syndrome have not changed over the last two decades and that mortality depends on the geographic location of studies.

Age-Dependent Changes in the Pulmonary Renin-Angiotensin System Are Associated With Severity of Lung Injury in a Model of Acute Lung Injury in Rats.

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.

Association between Maturation and Aging and Pulmonary Responses in Animal Models of Lung Injury: A Systematic Review.

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.

The effect of short-term high versus normal protein intake on whole-body protein synthesis and balance in children following cardiac surgery: a randomized double-blind controlled clinical trial.

BACKGROUND: Infants undergoing cardiac surgery are at risk of a negative protein balance, due to increased proteolysis in response to surgery and the cardiopulmonary bypass circuit, and limited intake. The aim of the study was to quantify the effect on protein kinetics of a short-term high-protein (HP) diet in infants following cardiac surgery. METHODS: In a prospective, double-blinded, randomized trial we compared the effects of a HP (5 g · kg(-1) · d(-1)) versus normal protein (NP, 2 g · kg(-1) · d(-1)) enteral diet on protein kinetics in children <24 months, on day 2 following surgical repair of congenital heart disease. Valine kinetics and fractional albumin synthesis rate (FSRalb) were measured with mass spectrometry using [1-(13)C]valine infusion. The Mann-Whitney U test was used to investigate differences between group medians. Additionally, the Hodges-Lehmann procedure was used to create a confidence interval with a point estimate of median differences between groups. RESULTS: Twenty-eight children (median age 9 months, median weight 7 kg) participated in the study, of whom in only 20 subjects isotopic data could be used for final calculations. Due to underpowering of our study, we could not draw conclusions on the primary outcome parameters. We observed valine synthesis rate of 2.73 (range: 0.94 to 3.36) and 2.26 (1.85 to 2.73) µmol · kg(-1) · min(-1) in the HP and NP diet, respectively. The net valine balance was 0.54 (-0.73 to 1.75) and 0.24 (-0.20 to 0.63) µmol · kg(-1) · min(-1) in the HP and NP group. Between groups, there was no difference in FSRalb. We observed increased oxidation and BUN in the HP diet, compared to the NP diet, as a plausible explanation of the metabolic fate of surplus protein. CONCLUSIONS: It is plausible that the surplus protein in the HP group has caused the increase of valine oxidation and ureagenesis, compared to the NP group. Because too few patients had completed the study, we were unable to draw conclusions on the effect of a HP diet on protein synthesis and balance. We present our results as new hypothesis generating data. TRIAL REGISTRATION: Dutch Trial Register NTR2334.

Parents who wish no further treatment for their child.

BACKGROUND: In the ethical and clinical literature, cases of parents who want treatment for their child to be withdrawn against the views of the medical team have not received much attention. Yet resolution of such conflicts demands much effort of both the medical team and parents. OBJECTIVE: To discuss who can best protect a child's interests, which often becomes a central issue, putting considerable pressure on mutual trust and partnership. METHODS: We describe the case of a 3-year-old boy with acquired brain damage due to autoimmune-mediated encephalitis whose parents wanted to stop treatment. By comparing this case with relevant literature, we systematically explored the pros and cons of sharing end-of-life decisions with parents in cases where treatment is considered futile by parents and not (yet) by physicians. CONCLUSIONS: Sharing end-of-life decisions with parents is a more important duty for physicians than protecting parents from guilt or doubt. Moreover, a request from parents on behalf of their child to discontinue treatment is, and should be, hard to over-rule in cases with significant prognostic uncertainty and/or in cases with divergent opinions within the medical team.

Effect of oxidative stress on respiratory epithelium from children with Down syndrome.

Children with Down syndrome are at high risk for acute respiratory distress syndrome. In Down syndrome, both regulation of inflammation and apoptosis, important in acute respiratory distress syndrome pathophysiology, are abnormal. This has been linked to an imbalance in free radical scavengers. We investigated the expression of free radical scavengers and the effect of oxidative stress in terms of apoptosis and inflammation in respiratory epithelium from children with Down syndrome compared with control subjects. We cultured primary nasal epithelial cells from Down syndrome children (n=12) and controls (n=17) and exposed them to oxidative stress by supplementing superoxide. First we showed that the expression of the free radical scavengers CuZn-superoxide dismutase was 28% higher (p=0.06), catalase was 36% lower (p=0.04) and glutathione peroxidase was 73% lower (p=0.004) in Down syndrome children compared with controls. We found no significant difference in apoptosis, between Down syndrome and control subjects after exposure to oxidative stress. We also found no significant difference in levels of interleukin (IL)-1ß, IL-6, IL-8, vascular endothelial growth factor and granulocyte colony-stimulating factor in primary nasal epithelial cell supernatant after exposure to oxidative stress between Down syndrome and control subjects. We found an imbalance in free radical scavengers in respiratory epithelial cells from children with Down syndrome, but this did not result in increased levels of either apoptosis or inflammation upon exposure to oxidative stress.

Imbalance between pulmonary angiotensin-converting enzyme and angiotensin-converting enzyme 2 activity in acute respiratory distress syndrome.

OBJECTIVE: Angiotensin-converting enzyme and its effector peptide angiotensin II have been implicated in the pathogenesis of acute respiratory distress syndrome. Recently, angiotensin-converting enzyme 2 was identified as the counter-regulatory enzyme of angiotensin-converting enzyme that converts angiotensin II into angiotensin-(1-7). The aim of this study was to determine pulmonary angiotensin-converting enzyme and angiotensin-converting enzyme 2 activity in patients with acute respiratory distress syndrome. DESIGN: Prospective observational pilot study. SETTING: A PICU of a university hospital. PATIENTS: Fourteen patients admitted, requiring mechanical ventilation for respiratory syncytial virus lower respiratory tract infection. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Two groups of patients were distinguished at admission: a group fulfilling the criteria for acute respiratory distress syndrome and a non-acute respiratory distress syndrome group. Angiotensin-converting enzyme and angiotensin-converting enzyme 2 activity were measured in bronchoalveolar lavage fluid. Patients with acute respiratory distress syndrome had increased angiotensin-converting enzyme activity and decreased angiotensin-converting enzyme 2 activity (p < 0.001) compared with the control group. CONCLUSION: It is shown for the first time that in acute respiratory distress syndrome, enhanced angiotensin-converting enzyme activity is paralleled by a reduced angiotensin-converting enzyme 2 activity, similar to that found in an experimental rat model of acute respiratory distress syndrome. The reduced angiotensin-converting enzyme 2 activity may be counteracted by restoring angiotensin-(1-7) level, thereby offering a novel treatment modality for this syndrome.

Acute respiratory distress syndrome leads to reduced ratio of ACE/ACE2 activities and is prevented by angiotensin-(1-7) or an angiotensin II receptor antagonist.

Acute respiratory distress syndrome (ARDS) is a devastating clinical syndrome. Angiotensin-converting enzyme (ACE) and its effector peptide angiotensin (Ang) II have been implicated in the pathogenesis of ARDS. A counter-regulatory enzyme of ACE, ie ACE2 that degrades Ang II to Ang-(1-7), offers a promising novel treatment modality for this syndrome. As the involvement of ACE and ACE2 in ARDS is still unclear, this study investigated the role of these two enzymes in an animal model of ARDS. ARDS was induced in rats by intratracheal administration of LPS followed by mechanical ventilation. During ventilation, animals were treated with saline (placebo), losartan (Ang II receptor antagonist), or with a protease-resistant, cyclic form of Ang-(1-7) [cAng-(1-7)]. In bronchoalveolar lavage fluid (BALF) of ventilated LPS-exposed animals, ACE activity was enhanced, whereas ACE2 activity was reduced. This was matched by enhanced BALF levels of Ang II and reduced levels of Ang-(1-7). Therapeutic intervention with cAng-(1-7) attenuated the inflammatory mediator response, markedly decreased lung injury scores, and improved lung function, as evidenced by increased oxygenation. These data indicate that ARDS develops, in part, due to reduced pulmonary levels of Ang-(1-7) and that repletion of this peptide halts the development of ARDS.

Granzyme A- and B-cluster deficiency delays acute lung injury in pneumovirus-infected mice.

Lower respiratory tract infection by the human pneumovirus respiratory syncytial virus is a frequent cause of acute lung injury in children. Severe pneumovirus disease in humans is associated with activation of the granzyme pathway by effector lymphocytes, which may promote pathology by exaggerating proapoptotic caspase activity and proinflammatory activity. The main goal of this study was to determine whether granzymes contribute to the development of acute lung injury in pneumovirus-infected mice. Granzyme-expressing mice and granzyme A- and B-cluster single- and double-knockout mice were inoculated with the rodent pneumovirus pneumonia virus of mice strain J3666, and were studied for markers of lung inflammation and injury. Expression of granzyme A and B is detected in effector lymphocytes in mouse lungs in response to pneumovirus infection. Mice deficient for granzyme A and the granzyme B cluster have unchanged virus titers in the lungs but show a significantly delayed clinical response to fatal pneumovirus infection, a feature that is associated with delayed neutrophil recruitment, diminished activation of caspase-3, and reduced lung permeability. We conclude that granzyme A- and B-cluster deficiency delays the acute progression of pneumovirus disease by reducing alveolar injury.

Electro-osmotic Drag and Thermodynamic Properties of Water in Hydrated Nafion Membranes from Molecular Dynamics.

One of the important parameters in water management of proton exchange membranes is the electro-osmotic drag (EOD) coefficient of water. The value of the EOD coefficient is difficult to justify, and available literature data on this for Nafion membranes show scattering from in experiments and simulations. Here, we use a classical all-atom model to compute the EOD coefficient and thermodynamic properties of water from molecular dynamics simulations for temperatures between 330 and 420 K, and for different water contents between λ = 5 and λ = 20. λ is the ratio between the moles of water molecules to the moles of sulfonic acid sites. This classical model does not capture the Grotthuss mechanism; however, it is shown that it can predict the EOD coefficient within the range of experimental values for λ = 5 where the vehicular mechanism dominates proton transfer. For λ > 5, the Grotthuss mechanism becomes dominant. To obtain the EOD coefficient, average velocities of water and ions are computed by imposing different electric fields to the system. Our results show that the velocities of water and hydronium scale linearly with the electric field, resulting in a constant ratio of ca. 0.4 within the error bars. We find that the EOD coefficient of water linearly increases from 2 at λ = 5 to 8 at λ = 20 and the results are not sensitive to temperature. The EOD coefficient at λ = 5 is within the range of experimental values, confirming that the model can capture the vehicular transport of protons well. At λ = 20, due to the absence of proton hopping in the model, the EOD coefficient is overestimated by a factor of 3 compared to experimental values. To analyze the interactions between water and Nafion, the partial molar enthalpies and partial molar volumes of water are computed from molecular dynamics simulations. At different water uptakes, multiple linear regression is used on raw simulation data within a narrow composition range of water inside the Nafion membrane. The partial molar volumes and partial molar excess enthalpies of water asymptotically approach the molar volumes and molar excess enthalpies of pure water for water uptakes above 5. This confirms the model can capture the bulklike behavior of water in the Nafion at high water uptakes.

Role of the Fas/FasL system in a model of RSV infection in mechanically ventilated mice.

Infection with respiratory syncytial virus (RSV) in children can progress to respiratory distress and acute lung injury necessitating mechanical ventilation (MV). MV enhances apoptosis and inflammation in mice infected with pneumonia virus of mice (PVM), a mouse pneumovirus that has been used as a model for severe RSV infection in mice. We hypothesized that the Fas/Fas ligand (FasL) system, a dual proapoptotic/proinflammatory system involved in other forms of lung injury, is required for enhanced lung injury in mechanically ventilated mice infected with PVM. C57BL/6 mice and Fas-deficient ("lpr") mice were inoculated intratracheally with PVM. Seven or eight days after PVM inoculation, the mice were subjected to 4 h of MV (tidal volume 10 ml/kg, fraction of inspired O(2) = 0.21, and positive end-expiratory pressure = 3 cm H(2)O). Seven days after PVM inoculation, exposure to MV resulted in less severe injury in lpr mice than in C57BL/6 mice, as evidenced by decreased numbers of polymorphonuclear neutrophils in the bronchoalveolar lavage (BAL), and lower concentrations of the proinflammatory chemokines KC, macrophage inflammatory protein (MIP)-1α, and MIP-2 in the lungs. However, when PVM infection was allowed to progress one additional day, all of the lpr mice (7/7) died unexpectedly between 0.5 and 3.5 h after the onset of ventilation compared with three of the seven ventilated C57BL/6 mice. Parameters of lung injury were similar in nonventilated mice, as was the viral content in the lungs and other organs. Thus, the Fas/FasL system was partly required for the lung inflammatory response in ventilated mice infected with PVM, but attenuation of lung inflammation did not prevent subsequent mortality.

Ventilator-induced inflammatory response in lipopolysaccharide-exposed rat lung is mediated by angiotensin-converting enzyme.

Angiotensin-converting enzyme (ACE) mediates the ventilator-induced inflammatory response in healthy lungs via angiotensin II (Ang II). A rat model was used to examine the role of ACE and Ang II in the inflammatory response during mechanical ventilation of preinjured (ie, lipopolysaccharide [LPS]-exposed) lungs. When indicated, rats were pretreated with the ACE inhibitor captopril and/or intratracheal administration of LPS. The animals were ventilated for 4 hours with moderate pressure amplitudes. Nonventilated animals served as controls. ACE activity and levels of Ang II and inflammatory mediators (interleukin-6, Cytokine-induced Neutrophil Chemoattractant (CINC)-3, interleukin-1beta, and interleukin-10) were determined in bronchoalveolar lavage fluid (BALF). The localization of ACE and Ang II type 1 receptor in lung tissue was determined by immunohistochemistry. The role of the Ang II pathway was assessed by using its receptor antagonist Losartan. Mechanical ventilation of LPS-exposed animals increased ACE activity and levels of inflammatory mediators in BALF compared with ventilated nonexposed and LPS-exposed nonventilated animals. Blocking ACE by captopril attenuated the lung inflammatory response. Furthermore, increased ACE activity in BALF was accompanied by increased levels of Ang II and enhanced expression of its receptor on alveolar cells. Blocking the Ang II receptor attenuated the inflammatory mediator response to a larger extent than by blocking ACE. In conclusion, during mechanical ventilation ACE, via Ang II, mediates the inflammatory response of both healthy and preinjured lungs.

Skin lesions in children admitted to the paediatric intensive care unit: an observational study.

We analysed, by a prospective observational study over a 3-year period, the frequency and character of dermatological symptoms and diseases in children admitted to a tertiary general paediatric intensive care unit (PICU) of a university hospital. Skin problems were observed in 42 of 1,800 children admitted. There was a large variability in dermatological diseases in the PICU. In the majority (23/42), the skin problem was a dermatological manifestation of an underlying illness that caused admission to the PICU, e.g. infection, vasculitis or drug reaction. In four of the seven children who died, a direct relation between the dermatological disease and the cause of death could be established. Although the number of patients with relevant dermatological problems was limited, we believe that a skilled paediatric dermatologist is able to contribute to the effectiveness of diagnostic and therapeutic processes in paediatric intensive care patients.

Potential role of soluble TRAIL in epithelial injury in children with severe RSV infection.

Lower respiratory tract infection by respiratory syncytial virus (RSV) is a frequent cause of acute lung injury in young children and infants. Studies in adults and animals suggest that tumor necrosis factor receptor (TNFR) ligands may mediate lung injury by causing apoptosis of epithelial cells. The main goal of the present study was to determine whether the TNF-related apoptosis-inducing ligand (Apo2L/TRAIL) pathway may be implicated in epithelial injury during severe RSV infection in children. We report elevated levels of soluble (s)TRAIL released by leukocytes in bronchoalveolar lavage fluid (BALF) of patients with RSV-associated respiratory failure (n = 22) as compared with mechanically ventilated patients without pulmonary illness (n = 7). Primary bronchial epithelial cells of children without pulmonary disease obtained by nonbronchoscopic cytobrushing expressed both death receptors TRAIL-R1 and -R2, and were found to be susceptible for cell death by human recombinant sTRAIL in vitro. Furthermore, BALF from a patient with RSV induced cell death in these cells, which was partly attenuated by inhibiting TRAIL signaling. These data suggest that the TRAIL pro-apoptotic pathway may contribute to lung epithelial injury in severe RSV infection in children.

Course and predictors of posttraumatic stress disorder in parents after pediatric intensive care treatment of their child.

OBJECTIVE: To study posttraumatic stress disorder (PTSD) in parents after unexpected pediatric intensive care unit (PICU) treatment of their child and to identify risk factors for its development. METHOD: Parents completed PTSD questionnaires 3 and 9 months (N = 190) after PICU treatment. Risk factors included pretrauma data, medical data, social demographics and posttraumatic stress responses at 3 months. RESULTS: In total, 30.3% of parents met criteria for subclinical PTSD and 12.6% for clinical PTSD at 3 months. Clinical PTSD prevalence rates did not change over time. At 9 months, 10.5% of parents still met criteria for PTSD. Number of earlier stressful life events, earlier psychosocial care and posttraumatic stress responses at 3 months predicted persistent subclinical and clinical PTSD. CONCLUSIONS: PICU admission is a stressful event associated with persistent parental PTSD. Assessment of risk factors can facilitate detection of persistent PTSD for early intervention.

Cleaved caspase-3 in lung epithelium of children who died with acute respiratory distress syndrome.

OBJECTIVE: To investigate the extent of cleaved caspase-3 immunostaining in lung epithelial cells in children with acute respiratory distress syndrome. DESIGN: Observational study in sixteen children who died with acute respiratory distress syndrome and diffuse alveolar damage. SETTING: Pediatric intensive care unit. PATIENTS: Sixteen children with fatal acute respiratory distress syndrome and diffuse alveolar damage. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Double immunohistochemistry for cleaved caspase-3 and (pan)cytokeratin in lung tissues obtained at autopsy. Spectral imaging was used for the quantification of immunohistochemistry colocalization of these markers. We found a wide range in the percentage of alveolar epithelial cell surface area with positive cleaved caspase-3 staining in the lungs of children with acute respiratory distress syndrome (from 1% to almost 20%). The degree of caspase-3 immunostaining in epithelial cells positively correlated with age. CONCLUSION: There is a high variability in the extent of classic apoptosis in lung epithelial cells in pediatric acute respiratory distress syndrome, potentially in part dependent on age.

An explorative study on quality of life and psychological and cognitive function in pediatric survivors of septic shock.

OBJECTIVE: To evaluate self-reported health-related quality of life, anxiety, depression, and cognitive function in pediatric septic shock survivors. DESIGN: A retrospective cohort study. SETTING: A 14-bed tertiary pediatric intensive care unit. PATIENTS: Children aged >or=8 yrs at the time of the follow-up who were admitted between 1995 and 2004 for septic shock. Inotropic and or vasoconstrictive agents were administered to these patients for >or=24 hrs. INTERVENTION: Health-related quality of life was assessed with the KIDSCREEN-52, anxiety with the State Trait Anxiety Inventory for Children, depression with the Children's Depression Inventory, and cognitive function with the cognitive scale of the TNO-AZL Children's Quality of Life Questionnaire Child Form. MEASUREMENTS AND MAIN RESULTS: Fifty of 82 eligible pediatric septic shock survivors were evaluated. The median age of the children at pediatric intensive care unit admission was 4.2 yrs (range, 0.0-17.0 yrs); the median age at follow-up was 10.7 yrs (range, 8.0-20.4 yrs). Health-related quality of life and anxiety scores were comparable to the age-related Dutch norm population. Depression scores were significantly better than the norm population, whereas cognitive function was significantly lower than the norm population. We found that 44% of the children had cognitive scores <25% of the norm population. Young age at the time of pediatric intensive care unit admission was predictive of cognitive problems, and cognitive problems were associated with lower emotional function. CONCLUSIONS: In this group of septic shock survivors, health-related quality of life, anxiety, and depression are equal to or slightly better than the age-related Dutch norm population. Cognitive function is decreased, especially in children admitted at younger ages. Follow-up studies with adequate neuropsychological testing are warranted to evaluate the association between septic shock, cognitive function, and risk factors for cognitive problems.

Age-dependent differences in pulmonary host responses in ARDS: a prospective observational cohort study.

BACKGROUND: Results from preclinical studies suggest that age-dependent differences in host defense and the pulmonary renin-angiotensin system (RAS) are responsible for observed differences in epidemiology of acute respiratory distress syndrome (ARDS) between children and adults. The present study compares biomarkers of host defense and RAS in bronchoalveolar lavage (BAL) fluid from neonates, children, adults, and older adults with ARDS. METHODS: In this prospective observational study, we enrolled mechanical ventilated ARDS patients categorized into four age groups: 20 neonates (< 28 days corrected postnatal age), 29 children (28 days-18 years), 26 adults (18-65 years), and 17 older adults (> 65 years of age). All patients underwent a nondirected BAL within 72 h after intubation. Activities of the two main enzymes of RAS, angiotensin converting enzyme (ACE) and ACE2, and levels of biomarkers of inflammation, endothelial activation, and epithelial damage were determined in BAL fluid. RESULTS: Levels of myeloperoxidase, interleukin (IL)-6, IL-10, and p-selectin were higher with increasing age, whereas intercellular adhesion molecule-1 was higher in neonates. No differences in activity of ACE and ACE2 were seen between the four age groups. CONCLUSIONS: Age-dependent differences in the levels of biomarkers in lungs of ARDS patients are present. Especially, higher levels of markers involved in the neutrophil response were found with increasing age. In contrast to preclinical studies, age is not associated with changes in the pulmonary RAS.

Surviving pediatric intensive care: physical outcome after 3 months.

OBJECTIVE: This study investigated the prevalence and nature of physical and neurocognitive sequelae in pediatric intensive care unit (PICU) survivors. DESIGN AND SETTING: Prospective follow-up study 3 months after discharge from a 14-bed tertiary PICU in The Netherlands. PATIENTS AND PARTICIPANTS: The families of 250 previously healthy children unexpectedly admitted to the PICU were invited to visit the outpatient follow-up clinic for structured medical examination of the child 3 months after discharge; 186 patients were evaluated. MEASUREMENTS AND RESULTS: Pediatric Cerebral Performance Category (PCPC) and Pediatric Overall Performance Category (POPC) values were determined at PICU discharge, at the outpatient follow-up clinic, and retrospectively before admission to the PICU. We found that 69% of children had physical sequelae. In 30% of cases these were caused by a previously unknown illness and in 39% by acquired morbidity. In 8% of the children the acquired morbidity was related to complications from PICU procedures. Three months after discharge 77% of the children had normal PCPC scores and 31% had normal POPC scores. CONCLUSIONS: Our results indicate that PICU survival may be associated with substantial physical sequelae. Structured follow-up research, preferably by multicenter studies, is warranted in PICU survivors.