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Purpose: Environmental phthalate exposure has been associated with attention deficit disorders in children. We hypothesized that in children treated in the pediatric intensive care unit (PICU), circulating phthalates leaching from indwelling medical devices contribute to their long-term attention deficit., Methods: Circulating plasma concentrations of di(2-ethylhexyl)phthalate (DEHP) metabolites were quantified in 100 healthy children and 449 children who had been treated in PICU and were neurocognitively tested 4 years later. In a development patient cohort (N = 228), a multivariable bootstrap study identified stable thresholds of exposure to circulating DEHP metabolites above which there was an independent association with worse neurocognitive outcome. Subsequently, in a second patient cohort (N = 221), the observed independent associations were validated., Results: Plasma concentrations of DEHP metabolites, which were virtually undetectable [0.029 (0.027-0.031) µmol/l] in healthy children, were 4.41 (3.76-5.06) µmol/l in critically ill children upon PICU admission (P < 0.001). Plasma DEHP metabolite concentrations decreased rapidly but remained 18 times higher until PICU discharge (P < 0.001). After adjusting for baseline risk factors and duration of PICU stay, and further for PICU complications and treatments, exceeding the potentially harmful threshold for exposure to circulating DEHP metabolites was independently associated with the attention deficit (all P ≤ 0.008) and impaired motor coordination (all P ≤ 0.02). The association with the attention deficit was confirmed in the validation cohort (all P ≤ 0.01). This phthalate exposure effect explained half of the attention deficit in post-PICU patients., Conclusions: Iatrogenic exposure to DEHP metabolites during intensive care was independently and robustly associated with the important attention deficit observed in children 4 years after critical illness. Clinicaltrials.gov identifier: NCT00214916.

Purpose: To assess the impact of the duration and intensity of episodes of increased intracranial pressure on 6-month neurological outcome in adult and paediatric traumatic brain injury., Methods: Analysis of prospectively collected minute-by-minute intracranial pressure and mean arterial blood pressure data of 261 adult and 99 paediatric traumatic brain injury patients from multiple European centres. The relationship of episodes of elevated intracranial pressure (defined as a pressure above a certain threshold during a certain time) with 6-month Glasgow Outcome Scale was visualized in a colour-coded plot., Results: The colour-coded plot illustrates the intuitive concept that episodes of higher intracranial pressure can only be tolerated for shorter durations: the curve that delineates the duration and intensity of those intracranial pressure episodes associated with worse outcome is an approximately exponential decay curve. In children, the curve resembles that of adults, but the delineation between episodes associated with worse outcome occurs at lower intracranial pressure thresholds. Intracranial pressures above 20 mmHg lasting longer than 37 min in adults, and longer than 8 min in children, are associated with worse outcomes. In a multivariate model, together with known baseline risk factors for outcome in severe traumatic brain injury, the cumulative intracranial pressure-time burden is independently associated with mortality. When cerebrovascular autoregulation, assessed with the low-frequency autoregulation index, is impaired, the ability to tolerate elevated intracranial pressures is reduced. When the cerebral perfusion pressure is below 50 mmHg, all intracranial pressure insults, regardless of duration, are associated with worse outcome., Conclusions: The intracranial pressure-time burden associated with worse outcome is visualised in a colour-coded plot. In children, secondary injury occurs at lower intracranial pressure thresholds as compared to adults. Impaired cerebrovascular autoregulation reduces the ability to tolerate intracranial pressure insults. Thus, 50 mmHg might be the lower acceptable threshold for cerebral perfusion pressure.

Purpose: Recalibration and determining discriminative power, internationally, of the existing delirium prediction model (PRE-DELIRIC) for intensive care patients., Methods: A prospective multicenter cohort study was performed in eight intensive care units (ICUs) in six countries. The ten predictors (age, APACHE-II, urgent and admission category, infection, coma, sedation, morphine use, urea level, metabolic acidosis) were collected within 24 h after ICU admission. The confusion assessment method for the intensive care unit (CAM-ICU) was used to identify ICU delirium. CAM-ICU screening compliance and inter-rater reliability measurements were used to secure the quality of the data., Results: A total of 2,852 adult ICU patients were screened of which 1,824 (64%) were eligible for the study. Main reasons for exclusion were length of stay <1 day (19.1%) and sustained coma (4.1%). CAM-ICU compliance was mean (SD) 82 ± 16% and inter-rater reliability 0.87 ± 0.17. The median delirium incidence was 22.5% (IQR 12.8-36.6%). Although the incidence of all ten predictors differed significantly between centers, the area under the receiver operating characteristic (AUROC) curve of the eight participating centers remained good: 0.77 (95% CI 0.74-0.79). The linear predictor and intercept of the prediction rule were adjusted and resulted in improved re-calibration of the PRE-DELIRIC model., Conclusions: In this multinational study, we recalibrated the PRE-DELIRIC model. Despite differences in the incidence of predictors between the centers in the different countries, the performance of the PRE-DELIRIC-model remained good. Following validation of the PRE-DELIRIC model, it may facilitate implementation of strategies to prevent delirium and aid improvements in delirium management of ICU patients.

Purpose: Despite their controversial role, corticosteroids (CS) are frequently administered to patients with H1N1 virus infection with severe respiratory failure secondary to viral pneumonia. We hypothesized that invasive pulmonary aspergillosis (IPA) is a frequent complication in critically ill patients with H1N1 virus infection and that CS may contribute to this complication., Methods: We retrospectively selected all adult patients with confirmed H1N1 virus infection admitted to the intensive care unit (ICU) of two tertiary care hospitals from September 2009 to March 2011. Differences in baseline factors, risk factors, and outcome parameters were studied between patients with and without IPA., Results: Of 40 critically ill patients with confirmed H1N1, 9 (23 %) developed IPA 3 days after ICU admission. Five patients had proven and four had probable IPA. Significantly more IPA patients received CS within 7 days before ICU admission (78 versus 23 %, p = 0.002). IPA patients also received significantly higher doses of CS before ICU admission [hydrocortisone equivalent 800 (360-2,635) versus 0 (0-0) mg, p = 0.005]. On multivariate analysis, use of CS before ICU admission was independently associated with IPA [odds ratio (OR) 14.4 (2.0-101.6), p = 0.007]., Conclusions: IPA was diagnosed in 23 % of critically ill patients with H1N1 virus infection after a median of 3 days after ICU admission. Our data suggest that use of CS 7 days before ICU admission is an independent risk factor for fungal superinfection. These findings may have consequences for clinical practice as they point out the need for increased awareness of IPA, especially in those critically ill H1N1 patients already receiving CS.

The prevalence of diabetes mellitus is currently at epidemic proportions and it is estimated that it will increase even further over the next decades. Although genetic predisposition and lifestyle choices are commonly accepted reasons for the occurrence of type 2 diabetes, it has recently been suggested that environmental pollutants are additional risk factors for diabetes development and this review aims to give an overview of the current evidence for this. More specifically, because of the crucial role of pancreatic beta cells in the development and progression of type 2 diabetes, the present work summarises the known effects of several compounds on beta cell function with reference to mechanistic studies that have elucidated how these compounds interfere with the insulin secreting capacity of beta cells. Oestrogenic compounds, organophosphorus compounds, persistent organic pollutants and heavy metals are discussed, and a critical reflection on the relevance of the concentrations used in mechanistic studies relative to the levels found in the human population is given. It is clear that some environmental pollutants affect pancreatic beta cell function, as both epidemiological and experimental research is accumulating. This supports the need to develop a solid and structured platform to fully explore the diabetes-inducing potential of pollutants.

Objective: Study of leukocyte activation and release of toxic mediators during extracorporeal circulation (ECC). ECC can be used to study the potential protective effect of a pharmacon against neutrophil-mediated lung injury. Clinical studies have indicated that N-acetylcysteine (NAC) may improve systemic oxygenation and reduce the need for ventilatory support when given to patients with acute lung injury., Design: Cardiac surgery patients were pretreated with high-dose NAC in order to assess the potential role of NAC to interfere with neutrophil-mediated inflammation and lung injury., Patients: 18 patients who underwent ECC: group 1 (n = 8) no premedication (only placebo); group 2 (n = 10) NAC (72 mg/kg i.v. as a bolus, later 72 mg/kg over 12 h)., Measurements and Results: In group 2, the partial pressure of oxygen in arterial blood/fractional inspired oxygen 4 h after surgery was significantly higher than in group 1 (213 +/- 31 vs 123 +/- 22; p = 0.044). NAC pretreatment prevented an increase in plasma neutrophil elastase activity (18.9 +/- 6.9 vs 49.9 +/- 5.6 ng/ml in group 1 at the end of ECC; p = 0.027). Release of myeloperoxidase (MPO) was not affected (group 1:1105 +/- 225 ng/ml vs group 2:1127 +/- 81 at the end of ECC; p = 0.63). At the end of ECC, total antigenic human neutrophil elastase (group 1:671 +/- 72 ng/ml vs group 2:579 +/- 134; p = 0.37) and complex formation between elastase and alpha 1-proteinase inhibitor were no different in the two groups. There were no significant difference in cellular composition and mediators in the lavage fluid, although values for total number of neutrophils, elastase, MPO and interleukin-8 were lower in group 2., Conclusion: Pretreatment with NAC may prevent lung injury by diminishing elastase activity. Since the release of mediators, especially MPO, is not affected, this diminished activity of elastase may be achieved by enhanced inactivation by antiproteases after initial treatment.

A case of oral ingestion of large doses of both the amphetamine-derivative 3,4-methylene dioxyethamphetamine (MDEA) and heroin is reported. Despite high serum levels of both drugs, the patient did not present with the classic signs and symptoms normally seen during intoxication with these drugs. The patient recovered after symptomatic treatment. The possibility that opposite pharmacological properties of the two drugs prevented the patients death is discussed.

Objective: Angiotensin-converting enzyme (ACE) is considered as a possible marker for endothelial cell damage in serum or bronchoalveolar lavage fluid. This hypothesis was tested during cardiac surgery and during the adult respiratory distress syndrome., Design: We used patients with an expected different degree of endothelial cell damage. ACE levels in serum and bronchoalveolar lavage fluid were compared with indirect markers of alveolo-capillary barrier integrity., Setting: Interdisciplinary team in a university hospital., Methods: 13 Cardiac surgery patients received no glucocorticoids and 13 others received 2 g methylprednisolone before extracorporeal circulation. Thirteen patients were used as controls and 15 patients had nonseptic adult respiratory distress syndrome. All underwent bronchoalveolar lavage for ACE determination., Results: At different times during surgery serum angiotensin-converting enzyme levels were not significantly different between the two groups. In post-operative bronchoalveolar lavage fluid, angiotensin-converting enzyme levels were significantly higher in patients who received corticoids (27.8 +/- 1.7 U/l, mean +/- SEM), compared to patients without corticoids (19.8 +/- 1.4 U/l), control patients (18.2 +/- 1.3 U/l) or patients with full blown non-septic adult respiratory distress syndrome (18.8 +/- 1.1 U/l). There were no correlations between lavage angiotensin-converting enzyme and other parameters for alveolo-capillary membrane integrity in the lavage fluid such as the number of neutrophil cells, albumin or protein concentration, and between lavage angiotensin-converting enzyme and PaO2/FIO2 ratio during lavage., Conclusion: Angiotensin-converting enzyme activity in serum or bronchoalveolar lavage fluid does not reflect damage of endothelial cells or damage of alveolocapillary integrity in acute pulmonary disease.

Thromboembolic complications may occur in inflammatory bowel disease. Recently, we had the opportunity to observe a case of a cerebral arterial thrombosis in a young patient with active ulcerative colitis. Investigation of blood coagulation revealed a temporary Protein C, Protein S and Factor II deficiency. To our knowledge, this is the first reported case of a temporary Protein C and S deficiency in a patient with thrombosis and inflammatory bowel disease.