A comparison of four different models of acute respiratory distress syndrome in sheep.

BACKGROUND: Acute respiratory distress syndrome (ARDS) can have various causes. The study objective was to investigate whether different pathophysiologic models of ARDS would show different respiratory, cardiovascular and inflammatory outcomes. METHODS: We performed a prospective, randomized study in 27 ventilated ewes inducing ARDS using three different techniques to mimic the pulmonary causes of ARDS (ARDSp): warm saline lavage (n = 6), intratracheal hydrochloric acid (HCl; n = 6), intratracheal albumin (n = 10), and one technique to mimic an extrapulmonary cause of ARDS (ARDSexp): intravenous lipopolysaccharide (LPS iv; n = 5). ARDS was defined when PaO2 was < 15 kPa (112 mmHg) when ventilated with PEEP 10 cm H2O and FiO2 = 1.0. The effects on gas exchange were investigated by calculating the oxygenation index (OI) and the ventilation efficacy index (VEI) every 30 min for a period of 4 h. Post mortem lung lavage was performed to obtain broncho-alveolar lavage fluid (BALF) to assess lung injury and inflammation. Lung injury and inflammation were assessed by measuring the total number and differentiation of leukocytes, the concentration of protein and disaturated phospholipids, and interleukine-6 and -8 in the BALF. Histology of the lung was evaluated by measuring the mean alveolar size, alveolar wall thickness and the lung injury score system by Matute-Bello et al., as markers of lung injury. The concentration of interleukin-6 was determined in plasma, as a marker of systematic inflammation. RESULTS: The OI and VEI were most affected in the LPS iv group and thereafter the HCl group, after meeting the ARDS criteria. Diastolic blood pressure was lowest in the LPS iv group. There were no significant differences found in the total number and differentiation of leukocytes, the concentration of protein and disaturated phospholipids, or interleukin-8 in the BALF, histology of the lung and the lung injury score. IL-6 in BALF and plasma was highest in the LPS iv group, but no significant differences were found between the other groups. It took a significantly longer period of time to meet the ARDS criteria in the LPS iv group. CONCLUSIONS: The LPS model caused the most severe pulmonary and cardiovascular insufficiency. Surprisingly, there were limited significant differences in lung injury and inflammatory markers, despite the different pathophysiological models, when the clinical definition of ARDS was applied.

Characteristics and Outcome of Children with Wilms Tumor Requiring Intensive Care Admission in First Line Therapy.

Survival rates are excellent for children with Wilms tumor (WT), yet tumor and treatment-related complications may require pediatric intensive care unit (PICU) admission. We assessed the frequency, clinical characteristics, and outcome of children with WT requiring PICU admissions in a multicenter, retrospective study in the Netherlands. Admission reasons of unplanned PICU admissions were described in relation to treatment phase. Unplanned PICU admissions were compared to a control group of no or planned PICU admissions, with regard to patient characteristics and short and long term outcomes. In a multicenter cohort of 175 children with an underlying WT, 50 unplanned PICU admissions were registered in 33 patients. Reasons for admission were diverse and varied per treatment phase. Younger age at diagnosis, intensive chemotherapy regimens, and bilateral tumor surgery were observed in children with unplanned PICU admission versus the other WT patients. Three children required renal replacement therapy, two of which continued dialysis after PICU discharge (both with bilateral disease). Two children died during their PICU stay. During follow-up, hypertension and chronic kidney disease (18.2 vs. 4.2% and 15.2 vs. 0.7%) were more frequently observed in unplanned PICU admitted patients compared to the other patients. No significant differences in cardiac morbidity, relapse, or progression were observed. Almost 20% of children with WT required unplanned PICU admission, with young age and treatment intensity as potential risk factors. Hypertension and renal impairment were frequently observed in these patients, warranting special attention at presentation and during treatment and follow-up.

Gut mucosal cell damage in meningococcal sepsis in children: relation with clinical outcome.

OBJECTIVE: The pathophysiological sequelae of meningococcal sepsis are mainly caused by deregulated microvasculature function, leading to impaired tissue blood flow. Because mature enterocytes are known to be susceptible to altered perfusion, we aimed to investigate: (1) the development of enterocyte damage; and (2) the relation between enterocyte damage and severity of disease and outcome in children with meningococcal sepsis. DESIGN: Retrospective human study. SETTING: Pediatric intensive care unit at a university hospital. PATIENTS: Nineteen consecutive children with meningococcal sepsis were studied during their pediatric intensive care unit stay. INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS Circulating levels of intestinal fatty acid binding protein, a small cytosolic protein constitutively present in mature enterocytes and released on cell injury, were assessed. Severity of disease was represented by meningococcal-specific Rotterdam Score, generic Pediatric Risk of Mortality II score, and circulating interleukin-6. Clinical outcome was measured by length of pediatric intensive care unit stay and number of ventilator days. Highest plasma intestinal fatty acid binding protein values were measured on pediatric intensive care unit stay admission. At the time of admission, eight of 19 patients had higher intestinal fatty acid binding protein plasma levels than the upper reference limit of 30 healthy volunteers. In all survivors, intestinal fatty acid binding protein levels declined to normal values within 12 hrs after starting intensive treatment, whereas the three nonsurvivors maintained elevated intestinal fatty acid binding protein plasma levels. A significant correlation was found among intestinal fatty acid binding protein and Rotterdam Score, Pediatric Risk of Mortality II, interleukin-6 at admission (Spearman's r = 0.402, p = .006; r = 0.243, p = .045; r = 0.687, p < .001, respectively). Next, a significant correlation was found between intestinal fatty acid binding protein and clinical outcome. CONCLUSIONS: Elevated plasma intestinal fatty acid binding protein is found in eight of 19 children with severe pediatric intensive care unit stay at the time of clinical presentation, suggesting the presence of enterocyte damage. Furthermore, prolonged enterocyte damage is found in nonsurvivors. Further studies are needed to clarify the potential role for assessment of plasma intestinal fatty acid binding protein in monitoring treatment of pediatric intensive care unit stay.

Influenza A-associated acute necrotising encephalopathy in a 10-year-old child.

We report an otherwise healthy 10-year-old boy who was brought to the emergency department with altered mental status, vomiting, diarrhoea and fever (39.5°C), without signs of meningitis. The CT scan revealed bilateral hypodensities of the thalamus and cerebellum, with diffuse oedema and slight compression of the brainstem and a triventricular hydrocephalus. Lumbar puncture and blood examination revealed markedly elevated protein level of 2.4 g/L in cerebrospinal fluid and high serum aminotransferase, characteristic of acute necrotising encephalopathy (ANE). The PCR of the nasopharyngeal swab was influenza A positive. Because of signs of high intracranial pressure, mannitol was given, an external ventricular drain was placed and subsequently, a posterior fossa craniectomy was performed. Postoperatively, he showed signs of cerebellar mutism with emotional instability and diminished speech. Six months after presentation, he showed full recovery. This case illustrates ANE as a rare complication of influenza A infection.

Obstructive sleep apnea in obese adolescents referred for bariatric surgery: association with metabolic and cardiovascular variables.

BACKGROUND: obstructive sleep apnea syndrome (OSA) is a well-described disease entity in adults, with a higher prevalence in severely obese individuals, while at the same time associated with several comorbidities independently of BMI. Literature regarding OSA in severely obese adolescents is qualitatively and quantitatively limited, possibly resulting in suboptimal diagnosis and treatment. METHODS: polysomnographic, demographic, anthropometric, and comorbidity-related data were prospectively collected in 56 adolescents with morbid obesity refractory to conservative treatment who presented for surgical therapy. Differences between adolescents with no/mild (apnea-hypopnea index (AHI) 0-4.9) and moderate/severe OSA (AHI ≥ 5.0) were evaluated using independent-samples t, chi-square or Fisher's exact tests. Multivariable linear regression analysis was performed to evaluate the association of several variables with AHI, corrected for BMI z-score. RESULTS: of the 53 included subjects, 48 (90.6%) showed some degree of sleep disordered breathing and 20 (37.7%) had moderate/severe OSA. Patients with moderate/severe OSA had on average a higher neck circumference (42.4 versus 40.1 cm, p = 0.008), higher BMI z-score (3.7 versus 3.4, p = 0.003), higher plasma triglyceride level (2.2 versus 1.5 mmol/L, p = 0.012), and lower IGF (29.6 versus 40.2 mmol/L, p = 0.010) than those with no/mild OSA. BMI z-score and plasma triglyceride levels were independently related to AHI. CONCLUSIONS: OSA is highly prevalent amongst morbidly obese adolescents and is strongly associated with BMI z-score. Elevated plasma triglyceride levels are associated with AHI, independent of BMI z-score.

Risk factors for intensive care admission in children with severe acute asthma in the Netherlands: a prospective multicentre study.

RATIONALE: Severe acute asthma (SAA) can be fatal, but is often preventable. We previously observed in a retrospective cohort study, a three-fold increase in SAA paediatric intensive care (PICU) admissions between 2003 and 2013 in the Netherlands, with a significant increase during those years of numbers of children without treatment of inhaled corticosteroids (ICS). OBJECTIVES: To determine whether steroid-naïve children are at higher risk of PICU admission among those hospitalised for SAA. Furthermore, we included the secondary risk factors tobacco smoke exposure, allergic sensitisation, previous admissions and viral infections. METHODS: A prospective, nationwide multicentre study of children with SAA (2-18 years) admitted to all Dutch PICUs and four general wards between 2016 and 2018. Potential risk factors for PICU admission were assessed using logistic regression analyses. MEASUREMENTS AND MAIN RESULTS: 110 PICU and 111 general ward patients were included. The proportion of steroid-naïve children did not differ significantly between PICU and ward patients. PICU children were significantly older and more exposed to tobacco smoke, with symptoms >1 week prior to admission. Viral susceptibility was not a significant risk factor for PICU admission. CONCLUSIONS: Children with SAA admitted to a PICU were comparable to those admitted to a general ward with respect to ICS treatment prior to admission. Preventable risk factors for PICU admission were >7 days of symptoms without adjustment of therapy and exposure to tobacco smoke. Physicians who treat children with asthma must be aware of these risk factors.

Plasma arginine and citrulline concentrations in critically ill children: strong relation with inflammation.

BACKGROUND: The amino acid arginine plays a key role in many metabolic processes in health and disease. Low arginine concentrations are found in various illnesses in children. OBJECTIVE: The objective was to investigate the relation between plasma concentrations of arginine (and precursor amino acids) and severity of inflammation in critically ill children. DESIGN: This was an observational cohort study in children with viral respiratory disease (n = 21; control group), accidental or surgical trauma (n = 19), or sepsis (n = 19) who were admitted to a pediatric intensive care unit. RESULTS: Plasma arginine and citrulline concentrations were lower in subjects with sepsis and trauma than in those with viral disease (arginine: 33 +/- 4, 37 +/- 4, and 69 +/- 8 micromol/L, respectively, P < 0.01 for both; citrulline: 10 +/- 1, 14 +/- 1, and 23 +/- 2 micromol/L, respectively, P < 0.01 for both) and correlated strongly and inversely with severity of inflammation as indicated by plasma CRP concentration (r = -0.645 and r = -0.660, respectively; P < 0.001 for both). During recovery, plasma arginine and citrulline concentrations increased and were strongly related to the reduction in inflammation as shown by the inverse correlation between arginine and citrulline concentrations and the CRP concentration on days 3 (r = -0.832 and r = -0.756, P < 0.001 for both) and 7 (r = -0.784 and r = -0.694, P < 0.001 for both). CONCLUSIONS: Plasma concentrations of arginine and citrulline are low during the acute phase of critical illness in children and normalize again during recovery. Plasma arginine and citrulline are strongly related to the severity of inflammation indicated by plasma CRP concentrations.

24-Hour protein, arginine and citrulline metabolism in fed critically ill children - A stable isotope tracer study.

BACKGROUND & AIMS: The reference method to study protein and arginine metabolism in critically ill children is measuring plasma amino acid appearances with stable isotopes during a short (4-8 h) time period and extrapolate results to 24-h. However, 24-h measurements may be variable due to critical illness related factors and a circadian rhythm could be present. Since only short duration stable isotope studies in critically ill children have been conducted before, the aim of this study was to investigate 24-h appearance of specific amino acids representing protein and arginine metabolism, with stable isotope techniques in continuously fed critically ill children. METHODS: In eight critically ill children, admitted to the pediatric (n = 4) or cardiovascular (n = 4) intensive care unit, aged 0-10 years, receiving continuous (par)enteral nutrition with protein intake 1.0-3.7 g/kg/day, a 24-h stable isotope tracer protocol was carried out. L-[ring-2H5]-phenylalanine, L-[3,3-2H2]-tyrosine, L-[5,5,5-2H3]-leucine, L-[guanido-15N2]-arginine and L-[5-13C-3,3,4,4-2H4]-citrulline were infused intravenously and L-[15N]-phenylalanine and L-[1-13C]leucine enterally. Arterial blood was sampled every hour. RESULTS: Coefficients of variation, representing intra-individual variability, of the amino acid appearances of phenylalanine, tyrosine, leucine, arginine and citrulline were high, on average 14-19% for intravenous tracers and 23-26% for enteral tracers. No evident circadian rhythm was present. The pattern and overall 24-h level of whole body protein balance differed per individual. CONCLUSIONS: In continuously fed stable critically ill children, the amino acid appearances of phenylalanine, tyrosine, leucine, arginine and citrulline show high variability. This should be kept in mind when performing stable isotope studies in this population. There was no apparent circadian rhythm. CLINICAL TRIAL REGISTER: NCT01511354 on clinicaltrials.gov.

Hyperglycemia in children with meningococcal sepsis and septic shock: the relation between plasma levels of insulin and inflammatory mediators.

CONTEXT: Hyperglycemia and insulin resistance are common findings in critically ill adult patients and are associated with increased morbidity and mortality. OBJECTIVES: The objective of this study was to investigate the hyperglycemic response to critical illness in children. DESIGN: The study was designed as an observational cohort study. SETTING: The study was set in a university-affiliated pediatric intensive care unit. PATIENTS: Six children with meningococcal sepsis (MS) without shock and 10 children with meningococcal septic shock (MSS) were patients. MAIN OUTCOME MEASURES: Differences in blood glucose levels (measured during 72 h after admission) and differences in plasma levels of glucoregulatory hormones (insulin, GH, IGF-I, cortisol, glucagons, leptin), soluble cytokine receptors (sTNF-R55, R75, sIL-1R2), and IL-6 (measured on d 3) between MS and MSS patients were assessed. RESULTS: Blood glucose levels on d 2 and 3 were higher in MSS patients than in MS patients [7.5 (3.9-13.0) vs. 5.1 (4.0-6.0) and 6.5 (4.0-9.9) vs. 5.5 (4.8-6.8) mmol/liter, both P < 0.05]. Maximum blood glucose values recorded in individual patients were higher in MSS patients [9.3 (6.5-13) vs. 7.2 (6.2-9.9), P < 0.05] and correlated with severity of illness (r = 0.833, P < 0.001). Insulin levels in MSS patients were significantly lower (7.2 vs. 19.0 mU/liter, P < 0.001), compatible with insufficient insulin response to hyperglycemia, whereas MS patients showed insulin resistance. Insulin levels correlated inversely with levels of sTNF-R55 and R75 (r = -0.814 and -0.878, both P < 0.001), suggesting suppression of the proinflammatory response on insulin secretion. CONCLUSION: Hyperglycemia associated with hypoinsulinemia rather than insulin resistance may be the normal pathophysiological response in acute MSS in children. Our study emphasizes that application of intensive insulin therapy in critically ill children demands further investigation.

Comparison of interhospital pediatric intensive care transport accompanied by a referring specialist or a specialist retrieval team.

OBJECTIVE: Interhospital transfers of critically ill pediatric patients in The Netherlands are accompanied by referring specialists or by specialist retrieval teams. We compared the interventions before and directly after transports and the complications and the equipment available during transports in the two groups. DESIGN AND SETTING: Prospective observational clinical study in pediatric intensive care units of Dutch university hospitals. PATIENTS: 249 pediatric patients requiring interhospital intensive care transport. METHODS: Data were collected on interhospital pediatric intensive care transports. We compared patient characteristics, interventions before and directly after transport, complications and equipment available during transport (137 accompanied by referring specialists, 112 by specialist retrieval teams). RESULTS: Interhospital transports accompanied by referring specialists had a longer average transport time (74.6 vs. 60.2 min), higher incidence of respiratory insufficiency (56.9% vs. 41.1%), and lower incidence of circulatory insufficiency (27.0% vs. 41.1%) than primary admission diagnoses. These transports had a lower percentage of ventilatory support (47.4% vs. 72.3%), higher need for acute interventions directly upon arrival on the pediatric ICU, and higher incidence of critical and serious complications. In 75% of the transfers accompanied by retrieval teams interventions before the transport were deemed to be necessary. During the transports accompanied by referring specialists the equipment and materials available proved rather limited. CONCLUSIONS: During pediatric intensive care transports accompanied by nontrained referring specialists there appears to be a higher incidence of complications, specialized equipment is more often not available, and more acute interventions are required upon arrival in the pediatric ICU.