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1.  Interleukin-6 as inflammatory marker referring to multiple organ dysfunction syndrome in severely injured children 
Despite the suggestion that the inflammatory response in traumatized children is functionally unique, prognostic markers predicting pediatric multiple organ failure are lacking. We intended to verify whether Interleukin-6 (IL-6) displays a pivotal role in pediatric trauma similar to adults.
Traumatized children less than 18 years of age with an Injury Severity Score >9 points and consecutive admission to the hospital’s pediatric intensive care unit were included. Organ function was evaluated according to the score by Marshall et al. while IL-6 levels were measured repetitively every morning.
59 traumatized children were included (8.4 ± 4.4 years; 57.6% male gender). Incidence of MODS was 11.9%. No differences were found referring to age, gender, injury distribution or overall injury severity between children with and without MODS. Increased IL-6 levels during hospital admission were associated with injury severity (Spearman correlation: r = 0.522, p < 0.001), while an inconsistent association towards the development of MODS was proven at that time point (Spearman correlation: r = 0.180, p = 0.231; Pearson's correlation: r = 0.297, p = 0.045). However, increased IL-6 levels during the first two days were no longer associated with the injury severity but a significant correlation to MODS was measured.
The presented prospective study is the first providing evidence for a correlation of IL-6 levels with injury severity and the incidence of MODS in traumatized children.
PMCID: PMC3942614  PMID: 24589345
Multiple trauma; Pediatric trauma; Multiple organ dysfunction syndrome; Multiple organ failure; MODS; Inflammatory response; Interleukin-6; IL-6
2.  In-line filtration minimizes organ dysfunction: New aspects from a prospective, randomized, controlled trial 
BMC Pediatrics  2013;13:21.
Infused particles induce thrombogenesis, impair microcirculation and modulate immune response. We have previously shown in critically ill children, that particle-retentive in-line filtration reduced the overall complication rate of severe events, length of stay and duration of mechanical ventilation. We now evaluated the influence of in-line filtration on different organ function and thereby elucidated the potential underlying pathophysiological effects of particle infusion.
In this single-centre, prospective, randomized controlled trial 807 critically ill children were assigned to either control (n = 406) or filter group (n = 401), the latter receiving in-line filtration for complete infusion therapy. Both groups were compared regarding the differences of incidence rates and its 95% confidence interval (CI) of different organ dysfunction as defined by the International Pediatric Sepsis Consensus Conference 2005.
The incidence rates of respiratory (−5.06%; 95% CI, −9.52 to −0.59%), renal (−3.87%; 95% CI, −7.58 to −0.15%) and hematologic (−3.89%; 95% CI, −7.26 to −0.51%) dysfunction were decreased in the filter group. No difference was demonstrated for the occurrence rates of cardiovascular, hepatic, or neurologic dysfunction between both groups.
In-line filtration has beneficial effects on the preservation of hematologic, renal and respiratory function in critically ill patients. The presented clinical data further support our hypothesis regarding potential harmful effects of particles. In critically ill patients infused particles may lead to further deterioration of the microcirculation, induce a systemic hypercoagulability and inflammation with consecutive negative effects on organ function.
Trial registration number; NCT00209768
PMCID: PMC3571889  PMID: 23384207
In-line filtration; Intensive care; Particle; Inflammation; Children; Organ dysfunction
3.  Recognition and management of abdominal compartment syndrome among German pediatric intensivists: results of a national survey 
Annals of Intensive Care  2012;2(Suppl 1):S8.
Several decades ago, the beneficial effects of goal-directed therapy, which include decompressive laparotomy (DL) and open abdomen procedures in cases of intra-abdominal hypertension (IAH) in children, were proven in the context of closures of abdominal wall defects and large-for-size organ transplantations. Different neonatologic and pediatric disease patterns are also known to be capable of increasing intra-abdominal pressure (IAP). Nevertheless, a considerable knowledge transfer regarding such risk factors has hardly taken place. When left undetected and untreated, IAH threatens to evolve into abdominal compartment syndrome (ACS), which is accompanied by a mortality rate of up to 60% in children. Therefore, the present study looks at the recognition and knowledge of IAH/ACS among German pediatric intensivists.
In June 2010, a questionnaire was mailed to the heads of pediatric intensive care units of 205 German pediatric hospitals.
The response rate was 62%. At least one case of IAH was reported by 36% of respondents; at least one case of ACS, by 25%. Compared with adolescents, younger critically ill children appeared to develop IAH/ACS more often. Routine measurements of IAP were said to be performed by 20% of respondents. Bladder pressure was used most frequently (96%) to assess IAP. Some respondents (17%) only measured IAP in cases of organ dysfunction and failure. In 2009, the year preceding this study, 21% of respondents claimed to have performed a DL. Surgical decompression was indicated if signs of organ dysfunction were present. This was also done in cases of at least grade III IAH (IAP > 15 mmHg) without organ impairment.
Although awareness among pediatricians appears to have been increasing over the last decade, definitions and guidelines regarding the diagnosis and management of IAH/ACS are not applied uniformly. This variability could express an ever present lack of awareness and solid prospective data.
PMCID: PMC3390295  PMID: 22873424
intra-abdominal pressure; intra-abdominal hypertension; abdominal compartment syndrome; children; intensive care unit; questionnaire; decompressive laparotomy.
4.  In-line filtration reduces severe complications and length of stay on pediatric intensive care unit: a prospective, randomized, controlled trial 
Intensive Care Medicine  2012;38(6):1008-1016.
Particulate contamination due to infusion therapy carries a potential health risk for intensive care patients.
This single-centre, prospective, randomized controlled trial assessed the effects of filtration of intravenous fluids on the reduction of complications in critically ill children admitted to a pediatric intensive care unit (PICU). A total of 807 subjects were randomly assigned to either a control (n = 406) or filter group (n = 401), with the latter receiving in-line filtration. The primary endpoint was reduction in the rate of overall complications, which included the occurrence of systemic inflammatory response syndrome (SIRS), sepsis, organ failure (circulation, lung, liver, kidney) and thrombosis. Secondary objectives were a reduction in the length of stay on the PICU and overall hospital stay. Duration of mechanical ventilation and mortality were also analyzed.
Analysis demonstrated a significant reduction in the overall complication rate (n = 166 [40.9 %] vs. n = 124 [30.9 %]; P = 0.003) for the filter group. In particular, the incidence of SIRS was significantly lower (n = 123 [30.3 %] vs. n = 90 [22.4 %]; P = 0.01). Moreover the length of stay on PICU (3.89 [95 % confidence interval 2.97−4.82] vs. 2.98 [2.33−3.64]; P = 0.025) and duration of mechanical ventilation (14.0 [5.6−22.4] vs. 11.0 [7.1−14.9] h; P = 0.028) were significantly reduced.
In-line filtration is able to avert severe complications in critically ill patients. The overall complication rate during the PICU stay among the filter group was significantly reduced. In-line filtration was effective in reducing the occurrence of SIRS. We therefore conclude that in-line filtration improves the safety of intensive care therapy and represents a preventive strategy that results in a significant reduction of the length of stay in the PICU and duration of mechanical ventilation ( number: NCT00209768).
Electronic supplementary material
The online version of this article (doi:10.1007/s00134-012-2539-7) contains supplementary material, which is available to authorized users.
PMCID: PMC3351606  PMID: 22527062
In-line filtration; SIRS; Intensive care; Particle; Inflammation; Children; Complication
5.  Impairment of renal function using hyperoncotic colloids in a two hit model of shock: a prospective randomized study 
Critical Care  2012;16(1):R16.
One of the therapeutic essentials in severe sepsis and septic shock is an adequate fluid replacement to restore and maintain circulating plasma volume, improve organ perfusion and nutritive microcirculatory flow. The type of solution to be used as a fluid replacement remains under discussion. The aim of the study was to evaluate the effects of clinically used fluid replacement solutions on renal function and inflammatory response.
A total of 23 anesthetized and ventilated female German Landrace pigs were investigated over 19 hours using a two-hit model that combined hemorrhagic and septic shock. The septic shock was induced using an Escherichia coli laden clot placed into the abdominal cavity. Infusions of 6% hydroxyethylstarch 130/0.42 in acetate (6% HES 130), 4% gelatin in acetate (4% gelatin) and 10% hydroxyethylstarch 200/0.5 in saline (10% HES200) compared to Ringer's acetate (RAc) were used for fluid replacement to maintain a central venous pressure of 12 mmHg. Ringer's acetate was also used in the sham-treated group (SHAM).
At study end the cardiac output (10% HES200 143 ± 48 ml/kgBW; 6% HES130 171 ± 47 ml/kgBW; RAc 137 ± 32 ml/kgBW; 4% gelatin 160 ± 42 ml/kgBW), as well as mean arterial pressure did not differ between groups. N-acetyl-beta-D-glucosamidase was significantly higher in the hydroxyethylstarch 200 (157 ± 115 U/g creatinine; P < 0.05) group compared to hydroxyethylstarch 130 (24 ± 9 U/g creatinine), Ringer's acetate (2 ± 3 U/g creatinine) and SHAM (21 ± 15 U/g creatinine) at the study's end. Creatinine significantly increased by 87 ± 84 percent of baseline in the 10% HES200 group compared to RAc and 6% HES130. We demonstrated in the histology of the kidneys a significant increase in osmotic-nephrosis like lesions for 4% gelatin compared to RAc, 6% HES130 and SHAM. Urine output was lowest in the 10% HES200 and 4% gelatin group, however not significantly.
Interleukin(IL)-6 levels were significantly elevated in the 10% HES200 group (3,845 ± 1,472 pg/ml) two hours after sepsis induction compared to all other groups (6% HES130 1,492 ± 604 pg/ml; RAc 874 ± 363 pg/ml; 4% gelatin 1,623 ± 1,242 pg/ml).
Despite similar maintenance of macrocirculation 6% hydroxyethylstarch 130/0.42 and Ringer's acetate significantly preserve renal function and attenuate tubular damage better than 10% hydroxyethylstarch 200/0.5 in saline.
PMCID: PMC3396252  PMID: 22277099
6.  Human protein C concentrate in the treatment of purpura fulminans: a retrospective analysis of safety and outcome in 94 pediatric patients 
Critical Care  2010;14(4):R156.
Purpura fulminans (PF) is a devastating complication of uncontrolled systemic inflammation, associated with high incidence of amputations, skin grafts and death. In this study, we aimed to clarify the clinical profile of pediatric patients with PF who improved with protein C (PC) treatment, explore treatment effects and safety, and to refine the prognostic significance of protein C plasma levels.
In Germany, patients receiving protein C concentrate (Ceprotin®, Baxter AG, Vienna, Austria) are registered. The database was used to locate all pediatric patients with PF treated with PC from 2002 to 2005 for this national, retrospective, multi-centered study.
Complete datasets were acquired in 94 patients, treated in 46 centers with human, non-activated protein C concentrate for purpura fulminans. PC was given for 2 days (median, range 1-24 days) with a median daily dose of 100 IU/kg. Plasma protein C levels increased from a median of 27% to a median of 71% under treatment. 22.3% of patients died, 77.7% survived to discharge. Skin grafts were required in 9.6%, amputations in 5.3%. PF recovered or improved in 79.8%, remained unchanged in 13.8% and deteriorated in 6.4%. Four adverse events occurred in 3 patients, none classified as severe. Non-survivors had lower protein C plasma levels (P < 0.05) and higher prevalence of coagulopathy at admission (P < 0.01). Time between admission and start of PC substitution was longer in patients who died compared to survivors (P = 0.03).
This retrospective dataset shows that, compared to historic controls, only few pediatric patients with PF under PC substitution needed dermatoplasty and/or amputations. Apart from epistaxis, no bleeding was observed. Although the data comes from a retrospective study, the evidence we present suggests that PC had a beneficial impact on the need for dermatoplasty and amputations, pointing to the potential value of carrying out a prospective randomised controlled trial.
PMCID: PMC2945140  PMID: 20723255
7.  Analysis of particulate contaminations of infusion solutions in a pediatric intensive care unit 
Intensive Care Medicine  2010;36(4):707-711.
To examine the physical properties and chemical composition of particles captured by in-line microfilters in critically ill children, and to investigate the inflammatory and cytotoxic effects of particles on endothelial cells (HUVEC) and macrophages in vitro.
Prospective, observational study of microfilters following their use in the pediatric intensive care unit. In vitro model utilizing cytokine assays to investigate the effects of particles on human endothelial cells and murine macrophages.
Twenty filter membranes from nine patients and five controls were examined by electron microscopy (EM) and energy dispersion spectroscopy (EDX). The average number of particles found on the surface of the used membranes was 550 cm2. EDX analysis confirmed silicon as a major particle constituent. Half of the filter membranes showed conglomerates containing an uncountable number of smaller particles. In vitro, glass particles were used to mimic the high silicon content particles. HUVEC and murine macrophages were exposed to different contents of particles, and cytokine levels were assayed to assess their immune response. Levels of interleukin-1beta, interleukin-6, interleukin-8, and tumor necrosis factor alpha were suppressed.
Particle contamination of infusion solutions exists despite a stringent infusion regiment. The number and composition of particles depends on the complexity of the applied admixtures. Beyond possible physical effects, the suppression of macrophage and endothelial cell cytokine secretion in vitro suggests that microparticle infusion in vivo may have immune-modulating effects. Further clinical trials are necessary to determine whether particle retention by in-line filtration has an influence on the outcome of intensive care patients.
Electronic supplementary material
The online version of this article (doi:10.1007/s00134-010-1775-y) contains supplementary material, which is available to authorized users.
PMCID: PMC2837187  PMID: 20165942
Contamination; Particle; Immune system; In-line filtration; Infusion therapy

Results 1-8 (8)