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Purpose: Guidelines recommend administering antibiotics within 1 h of sepsis recognition but this recommendation remains untested by randomized trials. This trial was set up to investigate whether survival is improved by reducing the time before initiation of antimicrobial therapy by means of a multifaceted intervention in compliance with guideline recommendations., Methods: The MEDUSA study, a prospective multicenter cluster-randomized trial, was conducted from July 2011 to July 2013 in 40 German hospitals. Hospitals were randomly allocated to receive conventional continuous medical education (CME) measures (control group) or multifaceted interventions including local quality improvement teams, educational outreach, audit, feedback, and reminders. We included 4183 patients with severe sepsis or septic shock in an intention-to-treat analysis comparing the multifaceted intervention (n = 2596) with conventional CME (n = 1587). The primary outcome was 28-day mortality., Results: The 28-day mortality was 35.1% (883 of 2596 patients) in the intervention group and 26.7% (403 of 1587 patients; p = 0.01) in the control group. The intervention was not a risk factor for mortality, since this difference was present from the beginning of the study and remained unaffected by the intervention. Median time to antimicrobial therapy was 1.5 h (interquartile range 0.1-4.9 h) in the intervention group and 2.0 h (0.4-5.9 h; p = 0.41) in the control group. The risk of death increased by 2% per hour delay of antimicrobial therapy and 1% per hour delay of source control, independent of group assignment., Conclusions: Delay in antimicrobial therapy and source control was associated with increased mortality but the multifaceted approach was unable to change time to antimicrobial therapy in this setting and did not affect survival.

Objective: To provide an update to "Surviving Sepsis Campaign Guidelines for Management of Sepsis and Septic Shock: 2012"., Design: A consensus committee of 55 international experts representing 25 international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict-of-interest (COI) policy was developed at the onset of the process and enforced throughout. A stand-alone meeting was held for all panel members in December 2015. Teleconferences and electronic-based discussion among subgroups and among the entire committee served as an integral part of the development., Methods: The panel consisted of five sections: hemodynamics, infection, adjunctive therapies, metabolic, and ventilation. Population, intervention, comparison, and outcomes (PICO) questions were reviewed and updated as needed, and evidence profiles were generated. Each subgroup generated a list of questions, searched for best available evidence, and then followed the principles of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system to assess the quality of evidence from high to very low, and to formulate recommendations as strong or weak, or best practice statement when applicable., Results: The Surviving Sepsis Guideline panel provided 93 statements on early management and resuscitation of patients with sepsis or septic shock. Overall, 32 were strong recommendations, 39 were weak recommendations, and 18 were best-practice statements. No recommendation was provided for four questions., Conclusions: Substantial agreement exists among a large cohort of international experts regarding many strong recommendations for the best care of patients with sepsis. Although a significant number of aspects of care have relatively weak support, evidence-based recommendations regarding the acute management of sepsis and septic shock are the foundation of improved outcomes for these critically ill patients with high mortality.

Objective: To provide an update to the "Surviving Sepsis Campaign Guidelines for Management of Severe Sepsis and Septic Shock," last published in 2008., Design: A consensus committee of 68 international experts representing 30 international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict of interest policy was developed at the onset of the process and enforced throughout. The entire guidelines process was conducted independent of any industry funding. A stand-alone meeting was held for all subgroup heads, co- and vice-chairs, and selected individuals. Teleconferences and electronic-based discussion among subgroups and among the entire committee served as an integral part of the development., Methods: The authors were advised to follow the principles of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to guide assessment of quality of evidence from high (A) to very low (D) and to determine the strength of recommendations as strong (1) or weak (2). The potential drawbacks of making strong recommendations in the presence of low-quality evidence were emphasized. Recommendations were classified into three groups: (1) those directly targeting severe sepsis; (2) those targeting general care of the critically ill patient and considered high priority in severe sepsis; and (3) pediatric considerations., Results: Key recommendations and suggestions, listed by category, include: early quantitative resuscitation of the septic patient during the first 6 h after recognition (1C); blood cultures before antibiotic therapy (1C); imaging studies performed promptly to confirm a potential source of infection (UG); administration of broad-spectrum antimicrobials therapy within 1 h of the recognition of septic shock (1B) and severe sepsis without septic shock (1C) as the goal of therapy; reassessment of antimicrobial therapy daily for de-escalation, when appropriate (1B); infection source control with attention to the balance of risks and benefits of the chosen method within 12 h of diagnosis (1C); initial fluid resuscitation with crystalloid (1B) and consideration of the addition of albumin in patients who continue to require substantial amounts of crystalloid to maintain adequate mean arterial pressure (2C) and the avoidance of hetastarch formulations (1B); initial fluid challenge in patients with sepsis-induced tissue hypoperfusion and suspicion of hypovolemia to achieve a minimum of 30 mL/kg of crystalloids (more rapid administration and greater amounts of fluid may be needed in some patients (1C); fluid challenge technique continued as long as hemodynamic improvement is based on either dynamic or static variables (UG); norepinephrine as the first-choice vasopressor to maintain mean arterial pressure ≥65 mmHg (1B); epinephrine when an additional agent is needed to maintain adequate blood pressure (2B); vasopressin (0.03 U/min) can be added to norepinephrine to either raise mean arterial pressure to target or to decrease norepinephrine dose but should not be used as the initial vasopressor (UG); dopamine is not recommended except in highly selected circumstances (2C); dobutamine infusion administered or added to vasopressor in the presence of (a) myocardial dysfunction as suggested by elevated cardiac filling pressures and low cardiac output, or (b) ongoing signs of hypoperfusion despite achieving adequate intravascular volume and adequate mean arterial pressure (1C); avoiding use of intravenous hydrocortisone in adult septic shock patients if adequate fluid resuscitation and vasopressor therapy are able to restore hemodynamic stability (2C); hemoglobin target of 7-9 g/dL in the absence of tissue hypoperfusion, ischemic coronary artery disease, or acute hemorrhage (1B); low tidal volume (1A) and limitation of inspiratory plateau pressure (1B) for acute respiratory distress syndrome (ARDS); application of at least a minimal amount of positive end-expiratory pressure (PEEP) in ARDS (1B); higher rather than lower level of PEEP for patients with sepsis-induced moderate or severe ARDS (2C); recruitment maneuvers in sepsis patients with severe refractory hypoxemia due to ARDS (2C); prone positioning in sepsis-induced ARDS patients with a PaO (2)/FiO (2) ratio of ≤100 mm Hg in facilities that have experience with such practices (2C); head-of-bed elevation in mechanically ventilated patients unless contraindicated (1B); a conservative fluid strategy for patients with established ARDS who do not have evidence of tissue hypoperfusion (1C); protocols for weaning and sedation (1A); minimizing use of either intermittent bolus sedation or continuous infusion sedation targeting specific titration endpoints (1B); avoidance of neuromuscular blockers if possible in the septic patient without ARDS (1C); a short course of neuromuscular blocker (no longer than 48 h) for patients with early ARDS and a PaO (2)/FI O (2) <150 mm Hg (2C); a protocolized approach to blood glucose management commencing insulin dosing when two consecutive blood glucose levels are >180 mg/dL, targeting an upper blood glucose ≤180 mg/dL (1A); equivalency of continuous veno-venous hemofiltration or intermittent hemodialysis (2B); prophylaxis for deep vein thrombosis (1B); use of stress ulcer prophylaxis to prevent upper gastrointestinal bleeding in patients with bleeding risk factors (1B); oral or enteral (if necessary) feedings, as tolerated, rather than either complete fasting or provision of only intravenous glucose within the first 48 h after a diagnosis of severe sepsis/septic shock (2C); and addressing goals of care, including treatment plans and end-of-life planning (as appropriate) (1B), as early as feasible, but within 72 h of intensive care unit admission (2C). Recommendations specific to pediatric severe sepsis include: therapy with face mask oxygen, high flow nasal cannula oxygen, or nasopharyngeal continuous PEEP in the presence of respiratory distress and hypoxemia (2C), use of physical examination therapeutic endpoints such as capillary refill (2C); for septic shock associated with hypovolemia, the use of crystalloids or albumin to deliver a bolus of 20 mL/kg of crystalloids (or albumin equivalent) over 5-10 min (2C); more common use of inotropes and vasodilators for low cardiac output septic shock associated with elevated systemic vascular resistance (2C); and use of hydrocortisone only in children with suspected or proven "absolute"' adrenal insufficiency (2C)., Conclusions: Strong agreement existed among a large cohort of international experts regarding many level 1 recommendations for the best care of patients with severe sepsis. Although a significant number of aspects of care have relatively weak support, evidence-based recommendations regarding the acute management of sepsis and septic shock are the foundation of improved outcomes for this important group of critically ill patients.

Objective: The Surviving Sepsis Campaign (SSC) developed guidelines and treatment bundles for the administration of steroids in adult septic shock. However, it is not clear how this has affected clinical practice or patient outcome., Design and Setting: The SSC has developed an extensive database to assess the overall effect of its guidelines on clinical practice and patient outcome. This analysis focuses on one particular element of the SSC's management bundle, namely, the administration of low-dose steroids in adult septic shock. This analysis was conducted on data submitted from January 2005 through March 2010 including 27,836 subjects at 218 sites., Main Results: A total of 17,847 (of the total 27,836) patients in the database required vasopressor therapy despite fluid resuscitation and therefore met the eligibility criteria for receiving low-dose steroids. A total of 8,992 patients (50.4 %) received low-dose steroids for their septic shock. Patients in Europe (59.4 %) and South America (51.9 %) were more likely to be prescribed low-dose steroids compared to their counterparts in North America (46.2 %, p < 0.001). The adjusted hospital mortality was significantly higher (OR 1.18, 95 % CI 1.09-1.23, p < 0.001) in patients who received low-dose steroids compared to those who did not. There was still an association with increased adjusted hospital mortality with low-dose steroids even if they were prescribed within 8 h (OR 1.23, 95 % CI 1.13-1.34, p < 0.001)., Conclusions: Steroids were commonly administered in the treatment of septic shock in this subset analysis of the Surviving Sepsis Campaign database. However, this was associated with an increase in adjusted hospital mortality.

Objective: The Surviving Sepsis Campaign (SSC or "the Campaign") developed guidelines for management of severe sepsis and septic shock. A performance improvement initiative targeted changing clinical behavior (process improvement) via bundles based on key SSC guideline recommendations on process improvement and patient outcomes., Design and Setting: A multifaceted intervention to facilitate compliance with selected guideline recommendations in the ICU, ED, and wards of individual hospitals and regional hospital networks was implemented voluntarily in the US, Europe, and South America. Elements of the guidelines were "bundled" into two sets of targets to be completed within 6 h and within 24 h. An analysis was conducted on data submitted from January 2005 through March 2008., Main Results: Data from 15,022 subjects at 165 sites were analyzed to determine the compliance with bundle targets and association with hospital mortality. Compliance with the entire resuscitation bundle increased linearly from 10.9% in the first site quarter to 31.3% by the end of 2 years (P<0.0001). Compliance with the entire management bundle started at 18.4% in the first quarter and increased to 36.1% by the end of 2 years (P = 0.008). Compliance with all bundle elements increased significantly, except for inspiratory plateau pressure, which was high at baseline. Unadjusted hospital mortality decreased from 37 to 30.8% over 2 years (P = 0.001). The adjusted odds ratio for mortality improved the longer a site was in the Campaign, resulting in an adjusted absolute drop of 0.8% per quarter and 5.4% over 2 years (95% CI, 2.5-8.4%)., Conclusions: The Campaign was associated with sustained, continuous quality improvement in sepsis care. Although not necessarily cause and effect, a reduction in reported hospital mortality rates was associated with participation. The implications of this study may serve as an impetus for similar improvement efforts.

Objective: To provide an update to the original Surviving Sepsis Campaign clinical management guidelines, "Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock," published in 2004., Design: Modified Delphi method with a consensus conference of 55 international experts, several subsequent meetings of subgroups and key individuals, teleconferences, and electronic-based discussion among subgroups and among the entire committee. This process was conducted independently of any industry funding., Methods: We used the GRADE system to guide assessment of quality of evidence from high (A) to very low (D) and to determine the strength of recommendations. A strong recommendation indicates that an intervention's desirable effects clearly outweigh its undesirable effects (risk, burden, cost), or clearly do not. Weak recommendations indicate that the tradeoff between desirable and undesirable effects is less clear. The grade of strong or weak is considered of greater clinical importance than a difference in letter level of quality of evidence. In areas without complete agreement, a formal process of resolution was developed and applied. Recommendations are grouped into those directly targeting severe sepsis, recommendations targeting general care of the critically ill patient that are considered high priority in severe sepsis, and pediatric considerations., Results: Key recommendations, listed by category, include: early goal-directed resuscitation of the septic patient during the first 6 hrs after recognition (1C); blood cultures prior to antibiotic therapy (1C); imaging studies performed promptly to confirm potential source of infection (1C); administration of broad-spectrum antibiotic therapy within 1 hr of diagnosis of septic shock (1B) and severe sepsis without septic shock (1D); reassessment of antibiotic therapy with microbiology and clinical data to narrow coverage, when appropriate (1C); a usual 7-10 days of antibiotic therapy guided by clinical response (1D); source control with attention to the balance of risks and benefits of the chosen method (1C); administration of either crystalloid or colloid fluid resuscitation (1B); fluid challenge to restore mean circulating filling pressure (1C); reduction in rate of fluid administration with rising filing pressures and no improvement in tissue perfusion (1D); vasopressor preference for norepinephrine or dopamine to maintain an initial target of mean arterial pressure > or = 65 mm Hg (1C); dobutamine inotropic therapy when cardiac output remains low despite fluid resuscitation and combined inotropic/vasopressor therapy (1C); stress-dose steroid therapy given only in septic shock after blood pressure is identified to be poorly responsive to fluid and vasopressor therapy (2C); recombinant activated protein C in patients with severe sepsis and clinical assessment of high risk for death (2B except 2C for post-operative patients). In the absence of tissue hypoperfusion, coronary artery disease, or acute hemorrhage, target a hemoglobin of 7-9 g/dL (1B); a low tidal volume (1B) and limitation of inspiratory plateau pressure strategy (1C) for acute lung injury (ALI)/acute respiratory distress syndrome (ARDS); application of at least a minimal amount of positive end-expiratory pressure in acute lung injury (1C); head of bed elevation in mechanically ventilated patients unless contraindicated (1B); avoiding routine use of pulmonary artery catheters in ALI/ARDS (1A); to decrease days of mechanical ventilation and ICU length of stay, a conservative fluid strategy for patients with established ALI/ARDS who are not in shock (1C); protocols for weaning and sedation/analgesia (1B); using either intermittent bolus sedation or continuous infusion sedation with daily interruptions or lightening (1B); avoidance of neuromuscular blockers, if at all possible (1B); institution of glycemic control (1B) targeting a blood glucose < 150 mg/dL after initial stabilization ( 2C ); equivalency of continuous veno-veno hemofiltration or intermittent hemodialysis (2B); prophylaxis for deep vein thrombosis (1A); use of stress ulcer prophylaxis to prevent upper GI bleeding using H2 blockers (1A) or proton pump inhibitors (1B); and consideration of limitation of support where appropriate (1D). Recommendations specific to pediatric severe sepsis include: greater use of physical examination therapeutic end points (2C); dopamine as the first drug of choice for hypotension (2C); steroids only in children with suspected or proven adrenal insufficiency (2C); a recommendation against the use of recombinant activated protein C in children (1B)., Conclusion: There was strong agreement among a large cohort of international experts regarding many level 1 recommendations for the best current care of patients with severe sepsis. Evidenced-based recommendations regarding the acute management of sepsis and septic shock are the first step toward improved outcomes for this important group of critically ill patients.

Objective: To determine the prevalence and mortality of ICU patients with severe sepsis in Germany, with consideration of hospital size., Design: Prospective, observational, cross-sectional 1-day point-prevalence study., Setting: 454 ICUs from a representative nationwide sample of 310 hospitals stratified by size. Data were collected via 1-day on-site audits by trained external study physicians. Visits were randomly distributed over 1 year (2003)., Patients: Inflammatory response of all ICU patients was assessed using the ACCP/SCCM consensus conference criteria. Patients with severe sepsis were followed up after 3 months for hospital mortality and length of ICU stay., Measurements and Results: Main outcome measures were prevalence and mortality. A total of 3,877 patients were screened. Prevalence was 12.4% (95% CI, 10.9-13.8%) for sepsis and 11.0% (95% CI, 9.7-12.2%) for severe sepsis including septic shock. The ICU and hospital mortality of patients with severe sepsis was 48.4 and 55.2%, respectively, without significant differences between hospital size. Prevalence and mean length of ICU stay of patients with severe sepsis were significantly higher in larger hospitals and universities (

Objective: To define the frequency and prognostic implications of SIRS criteria in critically ill patients hospitalized in European ICUs., Design and Setting: Cohort, multicentre, observational study of 198 ICUs in 24 European countries., Patients and Interventions: All 3,147 new adult admissions to participating ICUs between 1 and 15 May 2002 were included. Data were collected prospectively, with common SIRS criteria., Results: During the ICU stay 93% of patients had at least two SIRS criteria [respiratory rate (82%), heart rate (80%)]. The frequency of having three or four SIRS criteria vs. two was higher in infected than non-infected patients (p < 0.01). In non-infected patients having more than two SIRS criteria was associated with a higher risk of subsequent development of severe sepsis (odds ratio 2.6, p < 0.01) and septic shock (odds ratio 3.7, p < 0.01). Organ system failure and mortality increased as the number of SIRS criteria increased., Conclusions: Although common in the ICU, SIRS has prognostic importance in predicting infections, severity of disease, organ failure and outcome.

Objective: To develop management guidelines for severe sepsis and septic shock that would be of practical use for the bedside clinician, under the auspices of the Surviving Sepsis Campaign, an international effort to increase awareness and improve outcome in severe sepsis., Design: The process included a modified Delphi method, a consensus conference, several subsequent smaller meetings of subgroups and key individuals, teleconferences, and electronic-based discussion among subgroups and among the entire committee. The modified Delphi methodology used for grading recommendations built upon a 2001 publication sponsored by the International Sepsis Forum. We undertook a systematic review of the literature graded along 5 levels to create recommendation grades from A-E, with A being the highest grade. Pediatric considerations were provided to contrast adult and pediatric management., Participants: Participants included 44 critical care and infectious disease experts representing 11 international organizations., Results: A total of 46 recommendations plus pediatric management considerations., Conclusions: Evidence-based recommendations can be made regarding many aspects of the acute management of sepsis and septic shock that will hopefully translate into improved outcomes for the critically ill patient. The impact of these guidelines will be formally tested and guidelines updated annually, and even more rapidly when some important new knowledge becomes available.

Antibiotic-induced release of bacterial cell wall components can have immediate adverse effects for the patient. This article reviews the data on endotoxin release after initiation of antibiotic therapy and its role in the pathogenesis of sepsis and septic shock. Antibiotics differ in their potential to liberate endotoxins from bacterial cell walls. When used for treatment of systemic Gram-negative infection, some classes of beta-lactam antibiotics lead to markedly increased levels of free endotoxins while treatment with carbapenems and aminoglycosides produces relatively low amounts of endotoxins. Antibiotics that induce the formation of long, aberrant bacterial cells before effectively killing the microorganisms show the highest degree of endotoxin liberation. There is increasing evidence from animal models and clinical studies of sepsis that the antibiotic-mediated release of biologically active cell wall components derived from Gram-positive, Gram-negative or fungal organisms is associated with a rapid clinical deterioration.

Objectives: Several studies have demonstrated altered platelet function during nitric oxide inhalation (iNO) in adults and neonates. In vitro NO inhibits activation of fibrinogen receptor glycoprotein (GP) IIb/IIIa in a dose-dependent manner. In neonates GPIIb/IIIa response to stimulation is physiologically attenuated during the first days after birth in comparison to adults; the effects of NO on GPIIb/IIIa in neonates, however, are less established. We investigated the response of platelets from neonates, their mothers, and nonpregnant controls to the NO donor SIN-1 in vitro., Design: Umbilical cord and venous (mother, controls) platelet-rich plasma was stimulated in vitro with 10 microM ADP or 0.05 U/ml thrombin in the presence or absence of 10 microM SIN-1. GPIIb/IIIa activation was determined by two-color flow cytometry., Setting: Delivery department of an university hospital., Patients and Participants: Ten healthy term neonates, their mothers and nonpregnant controls., Measurements and Results: NO significantly reduced GPIIb/IIIa activation in thrombin- and ADP-stimulated platelets in all groups (p < 0.001). Neonatal platelets were significantly hyporeactive to stimulation (p < 0.05), but the relative response to SIN-1 was similar in all three groups (70 +/- 5 %)., Conclusions: The relative amount of NO-induced inhibition of GPIIb/ IIIa activation in neonates is thus similar to that of adults. However, due to the intrinsic hyporesponsiveness of neonatal platelets and NO-synergistic pharmacodynamic profiles of other drugs (e.g., prostacyclin), possible adverse effects of iNO must be considered.

Objective: To investigate nasal nitric oxide (NO) excretion, pulmonary NO excretion, and autoinhalation of nasally released NO at rest compared with that during moderate exercise in smokers and non-smokers., Design: Prospective observational study., Setting: University laboratory., Participants: Fourteen healthy adult volunteers., Interventions: Breathing of NO-purified air supplied via a tube system at rest and during a bicycle-ergometer workload of 60 Watt over a time of 10 min., Measurement and Results: We examined nasal and pulmonary NO excretion in smoking (n = 7) and non-smoking (n = 7) adult human volunteers. At rest, we measured constant nasal NO excretion rates of 311 +/- 89 nl/min for non-smokers and 261 +/- 142 nl/min for smokers (mean +/- SD, n.s.). During 60 W exercise, nasal NO release remained unchanged, while pulmonary NO excretion doubled compared with the rates at rest (non-smokers: 40 +/- 21 nl/min versus 23 +/- 14 nl/min, p < 0.05; smokers: 41 +/- 8 nl/min versus 22 +/- 8 nl/min, p < 0.05). The differences between smokers and non-smokers in nasal or pulmonary NO excretion were not significant. To determine the autoinhaled amount of nasally released NO, we also measured the NO concentration within the nasopharynx of five volunteers during nasal breathing. The average inhaled NO concentration was 17.8 +/- 3.1 ppb at rest and this decreased to 9.3 +/- 1.8 ppb during exercise of 60 W, while minute ventilation approximately doubled from 9 +/- 2 to 21 +/- 3 l/min., Conclusion: Our results demonstrate that moderate exercise increased exclusively pulmonary NO excretion. Nasal NO release, which is 10 times higher at rest, was not changed. The decrease in autoinhaled NO concentration during exercise results from dilution of the continuous nasal release by the increased respiratory gas flow. The individual NO release allows no conclusion about smoking habits.

Objective: To establish the safety of systemic Cancer Multistep Therapy (sCMT) including whole body hyperthermia, by means of hemodynamic, laboratory and clinical investigations., Design: Prospective study., Setting: University clinic., Patients: 12 patients with various cancers (with sCMT), a second group of 20 patients with colorectal carcinoma treated with chemotherapy (without sCMT)., Interventions: 25 treatments with sCMT for 60 min at 41.8 degrees C (including chemotherapy) were given in addition to induced hyperoxemia and hyperglycemia under general anesthesia., Measurements and Results: Invasive monitoring of systemic and pulmonary hemodynamics as well as pulmonary gas exchange was used at 37 degrees C, 40 degrees C, 41.8 degrees C and 39 degrees C. In addition, laboratory parameters were measured before and within 4 days of therapy. At 41.8 degrees C, invasive monitoring showed characteristic signs of hyperdynamic circulation. In addition, right-to-left shunt, oxygen consumption, oxygen delivery and lactate levels were significantly different from pretreatment values. At the end of therapy, lactate levels and the extravascular lung water index increased, whereas all other parameters showed a clear tendency to return to initial values. Within the first day after sCMT, we measured a slight but significant reversible increase in serum creatinine compared to pretreatment values, but found no significant alterations of other chemical parameters. Between the sCMT group and controls, there was only a temporary significant difference in aspartate aminotransferase levels 2 days after therapy., Conclusions: sCMT, including whole body hyperthermia, accompanied by suitable anesthesiological management and monitoring, does not lead to any serious or sustained organ dysfunction and can therefore be regarded as a safe therapy.

Objective: To determine whether the quality of infiltrations in chest radiographs can accurately predict the histological extent of fibrotic change in patients with acute respiratory distress syndrome (ARDS)., Design: Retrospective clinical investigation., Setting: Intensive care unit (ICU) of a university teaching hospital., Patients and Methods: Of 47 patients treated with extracorporeal membrane oxygenation (ECMO) for severe ARDS over a 5-year period, 23 patients underwent open lung biopsy at thoracotomy for treatment, mostly of pneumothorax. Chest films obtained by portable chest roentgenography preceding the operation were reviewed retrospectively and compared to the histomorphological results of the lung specimen., Results: Chest radiographs displayed mixed alveolar-reticular opacification in 60.2%, alveolar patterns in 22.9% and reticular opacities in 10.5%. In 0.4% there were no infiltrates, 6% could not be evaluated because of insufficient quality. There was no relevant difference between the right and left lungs. Subdividing patients into two groups according to the histological results of either absent or mild (1) or severe (2) lung fibrosis, we found an alveolar haziness in 12.3% in group 1 compared with 28.2% in group 2, while reticular characteristics were identified in 13% and 11%, respectively., Conclusions: The most common opacity in chest radiographs of patients with severe ARDS treated with ECMO is mixed alveolar-reticular opacification. Severe lung fibrosis is not positively correlated with a reticular radiographic pattern. ECMO does not lead to specific radiological changes in conventional radiograms, contrary to clinical findings that treatment with ECMO might induce pleural or pulmonic haemorrhage, especially in the earlier days when systemic heparinization had to be used instead of the heparin-coated tube-surfacing.

Objective: Nitric oxide (NO) has antithrombotic properties by regulating platelet function, whereas direct effects on plasmatic coagulation are rarely described. In sepsis and inflammation, when synthesis of NO, oxygen radicals and toxic metabolites is crucial, the expression of tissue factor (TF) on monocytes stimulated by lipopolysaccharides (LPS) induces intravascular coagulation. This study was performed to examine the influence of NO and the NO-dependent metabolite peroxynitrite on LPS-induced TF expression and activity in human monocytes., Design: Experimental study., Setting: Laboratory for cell biology., Methods: Human peripheral blood mononuclear cells were isolated from buffy coats by gradient centrifugation. The NO-releasing compounds SIN1 and NOC18 were used under different conditions. TF antigen was assayed by flow cytometry, and its activity by a clotting assay. TF-mRNA was measured by reverse transcriptase polymerase chain reaction (RT-PCR-ELISA)., Measurements and Results: Whereas NOC18, a pure NO donor, had no effect, SIN1, releasing both NO and superoxide (O2-), reduced TF expression and activity in a dose- and time-dependent manner; superoxide dismutase (SOD) reversed the SIN1-mediated effect. Adding the O2(-)-deliberating system hypoxanthin/xanthin oxidase (which had no significant effect per se) to NOC18, or using the NO and O2- reaction product peroxynitrite resulted in a reduction of TF expression. RT-PCR-ELISA indicated upregulation of TF-mRNA by SIN1 with a peak at 500 microM; higher doses had less effect., Conclusion: These data demonstrate an influence of NO on LPS-induced TF expression in monocytes by prior formation of peroxynitrite; furthermore, the balance between NO and O2- seems to play a crucial role.

Objective: We investigated whether a treatment according to a clinical algorithm could improve the low survival rates in acute respiratory distress syndrome (ARDS)., Design: Uncontrolled prospective trial., Setting: One university hospital intensive care department., Patients and Participants: 122 patients with ARDS, consecutively admitted to the ICU., Interventions: ARDS was treated according to a criteria-defined clinical algorithm. The algorithm distinguished two main treatment groups: The AT-sine-ECMO (advanced treatment without extracorporeal membrane oxygenation) groups (n = 73) received a treatment consisting of a set of advanced non-invasive treatment options, the ECMO treatment group (n = 49) received additional extracorporeal membrane oxygenation (ECMO) using heparin-coated systems., Measurements and Results: The groups differed in both APACHE II (16 +/- 5 vs 18 +/- 5 points, p = 0.01) and Murray scores (3.2 +/- 0.3 vs 3.4 +/- 0.3 points, p = 0.0001), the duration of mechanical ventilation prior to admission (10 +/- 9 vs 13 +/- 9 days, p = 0.0151), and length of ICU stay in Berlin (31 +/- 17 vs 50 +/- 36 days, p = 0.0016). Initial PaO2/FIO2 was 86 +/- 27 mm Hg in AT-sine-ECMO patients that improved to 165 +/- 107 mm Hg on ICU day 1, while ECMO patients showed an initial PaO2/FIO2 of 67 +/- 28 mm Hg and improvement to 160 +/- 102 mm Hg was not reached until ICU day 13. QS/QT was significantly higher in the ECMO-treated group and exceeded 50% during the first 14 ICU days. The overall survival rate in our 122 ARDS patients was 75%. Survival rates were 89% in the AT-sine ECMO group and 55% in the ECMO treatment group (p = 0.0000)., Conclusions: We conclude that patients with ARDS can be successfully treated with the clinical algorithm and high survival rates can be achieved.

Objective: To compare the effects of inhaled nitric oxide (NO) and an infusion of prostacyclin (PGI2) on right ventricular function in patients with severe acute respiratory distress syndrome (ARDS)., Design: Randomized prospective short-term study., Setting: Post-surgical ICU in an university hospital., Patients: 10 patients with severe ARDS referred to our hospital for intensive care., Interventions: In random sequence the patients inhaled NO at a concentration of 18 parts per million (ppm) followed by 36 ppm, and received an intravenous infusion of PGI2 (4 ng.kg-1.min-1)., Measurements and Results: Inhalation of 18 ppm NO reduced the mean (+/- SE) pulmonary artery pressure (PAP) from 33 +/- 2 to 28 +/- 1 mmHg (p = 0.008), increased right ventricular ejection fraction (RVEF), as assessed by thermodilution technique, from 28 +/- 2 to 32 +/- 2% (p = 0.005), decreased right ventricular end-diastolic volume index from 114 +/- 6 to 103 +/- 8 ml.m-2 (p = 0.005) and right ventricular end-systolic volume index from 82 +/- 4 to 70 +/- 5 ml.m-2 (p = 0.009). Mean arterial pressure (MAP) and cardiac index (CI) did not change significantly. The effects of 36 ppm NO were not different from the effects of 18 ppm NO. Infusion of PGI2 reduced PAP from 34 +/- 2 to 30 +/- 2 mmHg (p = 0.02), increased RVEF from 29 +/- 2 to 32 +/- 2% (p = 0.02). Right ventricular end-diastolic and end-systolic volume indices did not change significantly. MAP decreased from 80 +/- 4 to 70 +/- 5 mmHg (p = 0.03), and CI increased from 4.0 +/- 0.5 to 4.5 +/- 0.5 l.min-1.m-2 (p = 0.02)., Conclusions: Using a new approach to selective pulmonary vasodilation by inhalation of NO, we demonstrate in this group of ARDS patients that an increase in RVEF is not necessarily associated with a rise in CI. The increase in CI during PGI2 infusion is probably related to the systemic effect of this substance.

We report about our first experiences with a new device for continuous intra-arterial monitoring of blood gases in a patient with severe acute respiratory failure. This device facilitated continuous monitoring of PaO2, PaCO2 and pH while weaning the patient from extracorporeal membrane oxygenation (ECMO). Although sufficient oxygenation at FIO2 0.45 could be achieved after disconnection from ECMO, carbon dioxide elimination remained inadequate and resulted in severe respiratory acidosis. Within six hours, PaCO2 increased to 95 mmHg. Continuous monitoring of pH and PaCO2 helped to monitor CO2 retention and assisted the decision making process for reinstitution of ECMO.

Objective: To evaluate the lowest dose of inhaled nitric oxide (NO) in patients with adult respiratory distress syndrome (ARDS), which is able to improve arterial oxygenation more than 30% compared to baseline data., Design: Prospective, clinical study., Setting: Anesthesiological ICU in a university hospital., Patients: 3 consecutive patients with severe ARDS according to clinical and radiological signs., Interventions: Pressure-controlled ventilation with positive end-expiratory pressure of 8-12 cm H2O. Inhalation of NO was performed with a blender system and a Servo 300 ventilator. The lowest effective NO dose was defined by titrating the inspiratory NO dose until reaching a 30% improvement of PaO2/FiO2. This dose was used for the following continuous long-term NO inhalation; controls of efficacy by investigation of hemodynamics and blood gas exchange were performed initially and 2 times per patient after intervals of 3-5 days., Measurements and Results: Initial NO concentrations were found to be effective at 60, 100, and 230 parts per billion (ppb). In all measurements, arterial oxygenation was found to be elevated by NO inhalation with the initially evaluated dose compared to baseline data; in parallel, the venous admixture (Qva/Qt) was reduced. The O2 delivery increased, although O2 consumption and hemodynamics did not change. In 1 patient, interruption of NO inhalation caused remarkable increase of pulmonary resistance., Conclusions: The improvement of oxygenation by NO inhalation in ARDS does not require reduction of pulmonary resistance and can be performed using low doses in the ppb range, which has to be considered as probably non-toxic.

The general opinion on epidural anesthesia in obstetrics may be adversely affected by recent public controversies about the mother's situation during childbirth in hospital, which nowadays is often considered to be a highly technological, impersonal, or "unnatural" procedure. This assumption led us to conduct an inquiry on maternal assessment of obstetric epidural anesthesia and its relation to the clinical and social history. The study included 113 parturients, who received epidural anesthesia (on-demand epidural injections of bupivacaine 0.25%) for vaginal delivery. Mothers were asked to answer certain questions about this regimen (e.g. analgetic efficacy; difficulties in deciding on this method; recommendations to other parturients; opinion of the role of epidural anesthesia in obstetrics; choice of analgesic regimen for future childbirth) 1 day after delivery and 2 months later. Additional social and historical factors (e.g. education; profession; family status; preceding pregnancy, childbirth or abortion; complications during pregnancy or childbirth; duration of parturition) were used to reveal relevant statistical correlations. Sixty-five percent of the patients considered pain relief by epidural anesthesia as "good" or even "very good" during the first inquiry immediately after childbirth. Women who had undergone prior interruptions of pregnancy were less satisfied, probably because of their rather ambiguous attitude towards motherhood. With regard to the choice of analgesic regimen for future childbirth (50% of the patients had made a definite decision to have epidural anesthesia under this condition), those women were especially reserved who had suffered from complications during pregnancy and disapproved of it in the future.(ABSTRACT TRUNCATED AT 250 WORDS)

In 49 autopsies on patients with generalized malignant lymphomas a thorough histological examination of the CNS was performed. Isolated neoplastic foci were found in the CNS in 10 cases. It is believed that most of the tumour infiltrations in the CNS as a result of neoplastic transformation of local mesenchymal cells and are not blood-borne metastases.