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1.  Alterations of leptin in the course of inflammation and severe sepsis 
BMC Infectious Diseases  2012;12:217.
The adipokine leptin regulates energy expenditure, vascular function, bone and cartilage growth as well as the immune system and systemic inflammatory response. Several activating effects towards T cells, monocytes, endothelium cells and cytokine production have been reported suggesting a protective role of leptin in the setting of an acute systemic inflammation. However, the pathophysiological role of leptin during severe sepsis is currently not elucidated in detail. This study aims to investigate leptin expression in cultured human adipocytes within an inflammatory model and in patients suffering from severe sepsis and evaluates treatment effects of drotrecogin alpha (activated) (DAA), the recombinant form of human activated protein C.
In an in-vitro inflammatory model of adipocyte cell-culture the effect of DAA on leptin mRNA expression was evaluated. Synthesis of mRNA was measured by quantitative polymerase chain reaction (qPCR). Additionally, supernatants of these adipocytes as well as serum levels of adiponectin were measured in blood of 104 severe septic patients by ELISA-method. 26 patients were treated with DAA (DAA+), 78 patients were not treated with DAA (DAA-).
Stimulation of human adipocytes with TNF alpha over 6 and 24 hours resulted in a significant decrease by 46% and 59% of leptin mRNA transcripts compared to un-stimulated controls (p < 0.05). Leptin levels of supernatants of adipocyte culture decreased by 25% and 23% (p < 0.05) after incubation with TNF alpha after 6 and 24 hours. Incubation with DAA at 50 ng/ml DAA and 5 μg/ml doubled mRNA expression significantly at 24 hours (p < 0.05) but not at 6 hours. From day 1 to day 3 of sepsis, leptin levels increased in DAA+ compared to DAA- patients (p<0.10).
Leptin appears to be involved in the pathogenesis of a systemic inflammatory response during sepsis. Administration of DAA significantly increased leptin expression. The specific mechanism or even benefit of DAA towards leptin needs further ongoing research.
PMCID: PMC3462137  PMID: 22973876
Adipocytes; Drotrecogin alpha (activated); Leptin; mRNA; Sepsis; Supernatants
2.  Rationale and study design of PROVHILO - a worldwide multicenter randomized controlled trial on protective ventilation during general anesthesia for open abdominal surgery 
Trials  2011;12:111.
Post-operative pulmonary complications add to the morbidity and mortality of surgical patients, in particular after general anesthesia >2 hours for abdominal surgery. Whether a protective mechanical ventilation strategy with higher levels of positive end-expiratory pressure (PEEP) and repeated recruitment maneuvers; the "open lung strategy", protects against post-operative pulmonary complications is uncertain. The present study aims at comparing a protective mechanical ventilation strategy with a conventional mechanical ventilation strategy during general anesthesia for abdominal non-laparoscopic surgery.
The PROtective Ventilation using HIgh versus LOw positive end-expiratory pressure ("PROVHILO") trial is a worldwide investigator-initiated multicenter randomized controlled two-arm study. Nine hundred patients scheduled for non-laparoscopic abdominal surgery at high or intermediate risk for post-operative pulmonary complications are randomized to mechanical ventilation with the level of PEEP at 12 cmH2O with recruitment maneuvers (the lung-protective strategy) or mechanical ventilation with the level of PEEP at maximum 2 cmH2O without recruitment maneuvers (the conventional strategy). The primary endpoint is any post-operative pulmonary complication.
The PROVHILO trial is the first randomized controlled trial powered to investigate whether an open lung mechanical ventilation strategy in short-term mechanical ventilation prevents against postoperative pulmonary complications.
Trial registration
PMCID: PMC3104489  PMID: 21548927
3.  Evidence and consensus-based German guidelines for the management of analgesia, sedation and delirium in intensive care – short version 
Targeted monitoring of analgesia, sedation and delirium, as well as their appropriate management in critically ill patients is a standard of care in intensive care medicine. With the undisputed advantages of goal-oriented therapy established, there was a need to develop our own guidelines on analgesia and sedation in intensive care in Germany and these were published as 2nd Generation Guidelines in 2005. Through the dissemination of these guidelines in 2006, use of monitoring was shown to have improved from 8 to 51% and the use of protocol-based approaches increased to 46% (from 21%).
Between 2006–2009, the existing guidelines from the DGAI (Deutsche Gesellschaft für Anästhesiologie und Intensivmedizin) and DIVI (Deutsche Interdisziplinäre Vereinigung für Intensiv- und Notfallmedizin) were developed into 3rd Generation Guidelines for the securing and optimization of quality of analgesia, sedation and delirium management in the intensive care unit (ICU). In collaboration with another 10 professional societies, the literature has been reviewed using the criteria of the Oxford Center of Evidence Based Medicine. Using data from 671 reference works, text, diagrams and recommendations were drawn up. In the recommendations, Grade “A” (very strong recommendation), Grade “B” (strong recommendation) and Grade “0” (open recommendation) were agreed.
As a result of this process we now have an interdisciplinary and consensus-based set of 3rd Generation Guidelines that take into account all critically illness patient populations.
The use of protocols for analgesia, sedation and treatment of delirium are repeatedly demonstrated. These guidelines offer treatment recommendations for the ICU team. The implementation of scores and protocols into routine ICU practice is necessary for their success.
PMCID: PMC2830566  PMID: 20200655
guideline; evidence; analgesia; sedation; delirium; monitoring; treatment; intensive care
4.  Cardiorespiratory effects of spontaneous breathing in two different models of experimental lung injury: a randomized controlled trial 
Critical Care  2008;12(6):R135.
Acute lung injury (ALI) can result from various insults to the pulmonary tissue. Experimental and clinical data suggest that spontaneous breathing (SB) during pressure-controlled ventilation (PCV) in ALI results in better lung aeration and improved oxygenation. Our objective was to evaluate whether the addition of SB has different effects in two different models of ALI.
Forty-four pigs were randomly assigned to ALI resulting either from hydrochloric acid aspiration (HCl-ALI) or from increased intra-abdominal pressure plus intravenous oleic acid injections (OA-ALI) and were ventilated in PCV mode either with SB (PCV + SB) or without SB (PCV – SB). Cardiorespiratory variables were measured at baseline after induction of ALI and after 4 hours of treatment (PCV + SB or PCV – SB). Finally, density distributions and end-expiratory lung volume (EELV) were assessed by thoracic spiral computed tomography.
PCV + SB improved arterial partial pressure of oxygen/inspiratory fraction of oxygen (PaO2/FiO2) by a reduction in intrapulmonary shunt fraction in HCl-ALI from 27% ± 6% to 23% ± 13% and in OA-ALI from 33% ± 19% to 26% ± 18%, whereas during PCV – SB PaO2/FiO2 deteriorated and shunt fraction increased in the HCl group from 28% ± 8% to 37% ± 17% and in the OA group from 32% ± 12% to 47% ± 17% (P < 0.05 for interaction time and treatment, but not ALI type). PCV + SB also resulted in higher EELV (HCl-ALI: 606 ± 171 mL, OA-ALI: 439 ± 90 mL) as compared with PCV – SB (HCl-ALI: 372 ± 130 mL, OA-ALI: 192 ± 51 mL, with P < 0.05 for interaction of time, treatment, and ALI type).
SB improves oxygenation, reduces shunt fraction, and increases EELV in both models of ALI.
PMCID: PMC2646345  PMID: 18980696
5.  Cerebral haemodynamics and carbon dioxide reactivity during sepsis syndrome 
Critical Care  2007;11(6):R123.
Most patients with sepsis develop potentially irreversible cerebral dysfunctions. It is yet not clear whether cerebral haemodynamics are altered in these sepsis patients at all, and to what extent. We hypothesized that cerebral haemodynamics and carbon dioxide reactivity would be impaired in patients with sepsis syndrome and pathological electroencephalogram patterns.
After approval of the institutional ethics committee, 10 mechanically ventilated patients with sepsis syndrome and pathological electroencephalogram patterns underwent measurements of cerebral blood flow and jugular venous oxygen saturation before and after reduction of the arterial carbon dioxide partial pressure by 0.93 ± 0.7 kPa iu by ypervent ilation. The cerebral capillary closing pressure was determined from transcranial Doppler measurements of the arterial blood flow of the middle cerebral artery and the arterial pressure curve. A t test for matched pairs was used for statistical analysis (P < 0.05).
During stable mean arterial pressure and cardiac index, reduction of the arterial carbon dioxide partial pressure led to a significant increase of the capillary closing pressure from 25 ± 11 mmHg to 39 ± 15 mmHg (P < 0.001), with a consecutive decrease of blood flow velocity in the middle cerebral artery of 21.8 ± 4.8%/kPa (P < 0.001), of cerebral blood flow from 64 ± 29 ml/100 g/min to 39 ± 15 ml/100 g/min (P < 0.001) and of jugular venous oxygen saturation from 75 ± 8% to 67 ± 14% (P < 0.01).
In contrast to other experimental and clinical data, we observed no pathological findings in the investigated parameters of cerebral perfusion and oxygenation.
PMCID: PMC2246217  PMID: 18045492
6.  Spontaneous breathing with airway pressure release ventilation favors ventilation in dependent lung regions and counters cyclic alveolar collapse in oleic-acid-induced lung injury: a randomized controlled computed tomography trial 
Critical Care  2005;9(6):R780-R789.
Experimental and clinical studies have shown a reduction in intrapulmonary shunt with spontaneous breathing during airway pressure release ventilation (APRV) in acute lung injury. This reduction was related to reduced atelectasis and increased aeration. We hypothesized that spontaneous breathing will result in better ventilation and aeration of dependent lung areas and in less cyclic collapse during the tidal breath.
In this randomized controlled experimental trial, 22 pigs with oleic-acid-induced lung injury were randomly assigned to receive APRV with or without spontaneous breathing at comparable airway pressures. Four hours after randomization, dynamic computed tomography scans of the lung were obtained in an apical slice and in a juxtadiaphragmatic transverse slice. Analyses of regional attenuation were performed separately in nondependent and dependent halves of the lungs on end-expiratory scans and end-inspiratory scans. Tidal changes were assessed as differences between inspiration and expiration of the mechanical breaths.
Whereas no differences were observed in the apical slices, spontaneous breathing resulted in improved tidal ventilation of dependent lung regions (P < 0.05) and less cyclic collapse (P < 0.05) in the juxtadiaphragmatic slices. In addition, with spontaneous breathing, the end-expiratory aeration increased and nonaerated tissue decreased in dependent lung regions close to the diaphragm (P < 0.05 for the interaction ventilator mode and lung region).
Spontaneous breathing during APRV redistributes ventilation and aeration to dependent, usually well-perfused, lung regions close to the diaphragm, and may thereby contribute to improved arterial oxygenation. Spontaneous breathing also counters cyclic collapse, which is a risk factor for ventilation-associated lung injury.
PMCID: PMC1414014  PMID: 16356227
7.  Prone position in mechanically ventilated patients – the hard or the soft way? 
Critical Care  2005;9(3):253-254.
Prone positioning may even in patients without abdominal hypertension result in an increased intra-abdominal pressure (IAP). Previous research could not demonstrate a marked increase in IAP associated with cardiovascular, renal, or hepato-splanchnic dysfunction when patients were proned in air-cushioned beds. Michelet and colleagues in this issue of Critical Care report that the increase in IAP in the prone position depends on the used mattress type. Compared with air-cushion beds, conventional foam mattresses resulted in a greater increase in IAP which was associated with a decrease in the plasma diappearance rate of indocyanin green (PDRICG) indicating inadequate heptosplanchnic function.
PMCID: PMC1175901  PMID: 15987415
8.  Clinical review: Biphasic positive airway pressure and airway pressure release ventilation 
Critical Care  2004;8(6):492-497.
This review focuses on mechanical ventilation strategies that allow unsupported spontaneous breathing activity in any phase of the ventilatory cycle. By allowing patients with the acute respiratory distress syndrome to breathe spontaneously, one can expect improvements in gas exchange and systemic blood flow, based on findings from both experimental and clinical trials. In addition, by increasing end-expiratory lung volume, as occurs when using biphasic positive airway pressure or airway pressure release ventilation, recruitment of collapsed or consolidated lung is likely to occur, especially in juxtadiaphragmatic lung legions. Traditional approaches to mechanical ventilatory support of patients with acute respiratory distress syndrome require adaptation of the patient to the mechanical ventilator using heavy sedation and even muscle relaxation. Recent investigations have questioned the utility of sedation, muscle paralysis and mechanical control of ventilation. Furthermore, evidence exists that lowering sedation levels will decrease the duration of mechanical ventilatory support, length of stay in the intensive care unit, and overall costs of hospitalization. Based on currently available data, we suggest considering the use of techniques of mechanical ventilatory support that maintain, rather than suppress, spontaneous ventilatory effort, especially in patients with severe pulmonary dysfunction.
PMCID: PMC1065046  PMID: 15566621
acute respiratory distress syndrome; airway pressure release ventilation; biphasic positive airway pressure; mechanical ventilation
9.  Remifentanil for analgesia-based sedation in the intensive care unit 
Critical Care  2003;8(1):13-14.
Providing effective analgesia and adequate sedation is a generally accepted goal of intensive care medicine. Due to its rapid, organ independent and predictable metabolism the short acting opioid remifentanil might be particularly useful for analgesia-based sedation in the intensive care unit (ICU). This hypothesis was tested by two studies in this issue of Critical Care. The study by Breen et al. shows that remifentanil does not exert prolonged clinical effects when continuously infused in renal failure patients, although the weak acting metabolite remifentanil acid accumulates. The study by Muellejans et al. reports a multicenter trial comparing a remifentanil versus a fentanyl based regimen in ICU patients. With both substances a target analgesia and sedation level was reached, and no major differences were found when frequent assessments of the sedation level and according readjustments of doses were performed. These results are in accordance with other studies suggesting that the adherence to a clear analgesia-based sedation protocol might be more important then the choice of medications itself.
PMCID: PMC420067  PMID: 14975040
analgesia; sedation; remifentanil; organ failure

Results 1-9 (9)