I.V. APD421 (amisulpride) prevents postoperative nausea and vomiting: a randomized, double-blind, placebo-controlled, multicentre trial.

BACKGROUND: Postoperative nausea and vomiting (PONV) remain significant clinical problems for patients, especially nausea. The D2-antagonist droperidol was popular for prophylaxis until safety concerns limited its use. In early testing, APD421 (amisulpride for i.v. injection), a D2/D3-antagonist, has shown promising antiemetic efficacy at very low doses. We conducted a randomized, double-blind, dose-finding study to investigate APD421 in PONV prophylaxis. METHODS: Adult surgical patients with ≥2 Apfel risk factors for PONV undergoing surgery expected to last ≥1 h and receiving standard inhalation anaesthesia were randomized to receive placebo or one of three doses of APD421 (1, 5, or 20 mg) as a single i.v. administration at anaesthesia induction. The primary endpoint was PONV (vomiting/retching or antiemetic rescue) in the 24 h period after surgery. RESULTS: Two hundred and fifteen patients received study drug, 92% female and 60% with ≥3 risk factors. Groups were well balanced for baseline characteristics and risk factors. The PONV incidence was 37/54 [69%; 90% confidence interval (CI), 57-79%] in the placebo group; 28/58 (48%; 90% CI, 37-60%) with 1 mg APD421 (P=0.048); 20/50 (40%; 90% CI, 28-53%) with 5 mg (P=0.006); and 30/53 (57%; 90% CI, 44-68%) with 20 mg (P>0.1). APD421 at 5 mg also significantly improved vomiting, rescue medication use, and nausea rates. The safety profile of APD421 was similar to that of placebo at all doses, with no significant central nervous system (CNS) or cardiac side-effects. CONCLUSIONS: APD421 given i.v. before surgery is safe and effective at reducing PONV in moderate/high-risk adult surgical patients. The optimal dose tested was 5 mg.

Time course of organ failure in patients with septic shock treated with hydrocortisone: results of the Corticus study.

INTRODUCTION: Corticosteroids have been proposed to decrease morbidity and mortality in patients with septic shock. An impact on morbidity should be anticipated to be earlier and more easily detected than the impact on mortality. METHODS: Prospective, randomized, double-blind, placebo-controlled study of 28-day mortality in patients with septic shock for <72 h who underwent a short high-dose ACTH test in 52 centers in 9 European countries. Patients received 11-day treatment with hydrocortisone or placebo. Organ dysfunction/failure was quantified by the use of the sequential organ failure assessment (SOFA) score. RESULTS: From March 2002 to November 2005, 499 patients were enrolled (hydrocortisone 251, placebo 248). Both groups presented a similar SOFA score at baseline (hydrocortisone 10.8 ± 3.2 vs. placebo 10.7 ± 3.1 points). There was no difference in 28-day mortality between the two treatment groups (hydrocortisone 34.3% vs. placebo 31.5%). There was a decrease in the SOFA score of hydrocortisone-treated patients from day 0 to day 7 compared to the placebo-treated patients (p = 0.0027), driven by an improvement in cardiovascular organ dysfunction/failure (p = 0.0005) and in liver failure (p < 0.0001) in the hydrocortisone-treated patients. CONCLUSION: Patients randomized to treatment with hydrocortisone demonstrated a faster decrease in total organ dysfunction/failure determined by the SOFA score, primarily driven by a faster improvement in cardiovascular organ dysfunction/failure. This organ dysfunction/failure improvement was not accompanied by a decreased mortality.

[Corticosteroid insufficiency in the critically ill. Pathomechanisms and recommendations for diagnosis and treatment]. / Kortikosteroidinsuffizienz bei kritisch Kranken. Pathomechanismen und Empfehlungen zur Diagnose und Behandlung.

Critically ill patients with severe systemic inflammation can develop critical illness-related corticosteroid insufficiency (CIRCI), which is associated with a poor outcome. A task force of the American College of Critical Care Medicine compiled recommendations for diagnosis and treatment of this clinical entity thereby focusing on patients with septic shock and acute respiratory distress syndrome (ARDS). The results of large scale multi-centre trials gave partially conflicting results arguing against the broad use of corticosteroids in stress doses. However, the task force recommended treatment with stress-dose corticosteroids in patients with septic shock who respond poorly to fluid resuscitation and vasopressor therapy and in patients with early ARDS (<14 days after onset). The dose of corticosteroids should be reduced in a step-wise manner. Corticosteroids at stress doses are currently under investigation in other target populations of critically ill patients potentially suffering from CIRCI. Preliminary data suggest that patients with vasodilatory shock after cardiac surgery and patients with liver cirrhosis and sepsis can benefit from corticosteroids. Critical illness-related corticosteroid insufficiency can also occur in patients with trauma, traumatic brain injury, acute pancreatitis and burn injuries, but data from clinical trials on these target groups are insufficient at present. The therapeutic use of corticosteroids in stress doses reduces the incidence of post-traumatic stress disorder (PTSD) after intensive care treatment.

Intraoperative thoracic epidural anaesthesia attenuates stress-induced immunosuppression in patients undergoing major abdominal surgery.

BACKGROUND: Intraoperative stress may suppress the adaptive immune system. Abolished proinflammatory lymphocyte function is associated with higher risk of infection and postoperative complications. We hypothesized that thoracic epidural anaesthesia (TEA) reduces intraoperative stress and thus attenuates lymphocyte decrease and impairment of proinflammatory lymphocyte function. METHODS: Fifty-four patients undergoing major abdominal surgery who had a thoracic epidural catheter inserted were studied. In the TEA-I group, this catheter was used for intraoperative analgesia, whereas the TEA-P group received systemic opioids during surgery. In both groups, patient-controlled epidural analgesia was used for postoperative pain management. Blood samples for immune analyses were obtained before induction of anaesthesia, 2 h after skin incision, and at days 1 and 4 after surgery. Lymphocyte subpopulations, expression of human leucocyte antigen (HLA)-DR on monocytes, plasma concentrations of interleukin (IL)-10, interferon-gamma (IFN-gamma), and IL-12, and concanavalin-A-stimulated concentrations of IFN-gamma and IL-10 were measured. Intraoperative data including bispectral index and plasma concentrations of epinephrine/cortisol were analysed; APACHE-II, SAPS II, and additional postoperative data were documented. RESULTS: Plasma concentrations of epinephrine and cortisol were significantly lower in the TEA-I patients during surgery. IFN-gamma/IL-10 ratio was significantly higher in the TEA-I group from 2 h after skin incision until day 1. Lymphocyte numbers and T-helper cells were significantly higher in the TEA-I group at day 1, whereas no significant differences were detected among IL-12, HLA-DR, and postoperative clinical course. CONCLUSIONS: Intraoperative use of thoracic epidural catheter reduced stress response and prevented stress-induced perioperative impairment of proinflammatory lymphocyte function.

["Asleep-awake-asleep"-anaesthetic technique for awake craniotomy]. / "Schlaf-Wach-Schlaf"-Technik zur CS Wachkraniotomie.

Awake craniotomy in tumor and epilepsy surgery or for the implantation of electrodes for deep brain stimulation requires specific anesthesiological strategies. Propofol allows for quick emergence and has little effect on the respiratory function of the usually spontaneously breathing patient. Pain control may be instituted by hemiscalp block for trepanation or local infiltration for deep brain electrode implantation. In addition, low dose remifentanil is recommended for trepanation (i.e. tumor or epilepsy surgery). The airway may be secured by an ordinary Magill tube placed transnasally with its tip underneath the epiglottis. To protect the patient against vomiting an adequate antiemetic prophylaxis is required.

Corticosteroids for treating severe sepsis and septic shock.

BACKGROUND: Sepsis may be complicated by impaired corticosteroid production. Giving corticosteroids could potentially benefit patients. OBJECTIVES: To examine the effects of corticosteroids on death at one month in patients with severe sepsis and septic shock. SEARCH STRATEGY: We searched the Cochrane Infectious Diseases Group's trial register (August 2003), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 3, 2003), MEDLINE (August 2003), EMBASE (August 2003), LILACS (August 2003), reference lists of articles, and also contacted trial authors. SELECTION CRITERIA: Randomized and quasi-randomized controlled trials of corticosteroids versus placebo or supportive treatment in severe sepsis and septic shock. DATA COLLECTION AND ANALYSIS: Two pairs of reviewers agreed the eligibility of trials. One reviewer extracted data, which was checked by the other reviewers and the primary author of the paper whenever possible. We obtained some missing data from the trial authors. We assessed trial methodological quality. MAIN RESULTS: We identified 15 trials (n =2023). Corticosteroids did not change 28-day all-cause mortality (15 trials, n = 2022, relative risk (RR) 0.92, 95% confidence interval (CI) 0.75 to 1.14; random effects model) and hospital mortality (13 trials, n = 1418, RR 0.89, 95% CI 0.71 to 1.11; random effects model); however, there was statistically significant heterogeneity, with some evidence that this was related to the dosing strategy. Corticosteroids reduced intensive care unit mortality (4 trials, n = 425, RR 0.83, 95% CI 0.70 to 0.97), increased the proportion of shock reversal by day 7 (6 trials, n = 728, RR 1.22, 95% CI 1.06 to 1.40) and by day 28 (4 trials, n = 425, RR 1.26, 95% CI 1.04 to 1.52), without increasing the rate of gastroduodenal bleeding (10 trials, n = 1321, RR 1.16, 95% CI 0.82 to 1.65), superinfection (12 trials, n = 1705, RR 0.93, 95% CI 0.73 to 1.18), and of hyperglycaemia (6 trials, n = 608, RR 1.22, 0.84 to 1.78). REVIEWER'S CONCLUSIONS: Overall, corticosteroids did not change 28-day mortality and hospital mortality in severe sepsis and septic shock. Long course of low dose corticosteroids reduced 28-day all-cause mortality, and intensive care unit and hospital mortality.

Response of neonatal platelets to nitric oxide in vitro.

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.

Early detection of increased tumour necrosis factor alpha (TNFalpha) and soluble TNF receptor protein plasma levels after trauma reveals associations with the clinical course.

BACKGROUND: The inflammatory response after trauma includes tumour necrosis factor alpha (TNFalpha) as pro-inflammatory cytokine. Furthermore, both soluble TNF receptor proteins (sTNF-R1 and sTNF-R2) were described to influence the post-traumatic inflammatory response and organ dysfunction. METHOD: From 47 trauma patients, blood samples were obtained at the scene of accident, at hospital admission, after 4 h, 12 h, and 24 h, and daily until day 6. Plasma levels of TNFalpha, sTNFR1 and sTNF-R2 were measured by enzyme immunoassay (EIA) and analysed comparing clinical parameters such as injury scores (ISS, AIS), development of multiple organ dysfunction syndrome (MODS) and/or systemic inflammatory response syndrome (SIRS), and outcome. RESULTS: Significant changes were observed in a time-dependent manner: TNFalpha and soluble TNF receptor levels were elevated compared to values of healthy persons. At 4 h after trauma, TNFalpha and sTNF-R2 showed an increase from initial values, which continued during the entire observation period. Severe trauma led to enhanced sTNF-R1 levels on scene and on hospital admission. Development of SIRS along with elevated sTNF-R1 began on scene and was present on admission, with increased sTNF-R2 from day 1 to day 4. MODS (until day 6) was preceded by increased sTNF-R2 levels on admission and up to 4 h after trauma. Outcome was associated neither with TNFalpha nor with soluble TNF receptor levels. CONCLUSION: Thus, in trauma patients, early post-traumatic MODS and SIRS coincide with increased levels of TNFalpha and TNF receptor proteins, revealing different, time-dependent changes. Hence, detection of TNFalpha and soluble TNF receptor proteins after trauma should pay regard to the time point of sampling.

Immunocompetence in the critically ill: understanding the problem.

The author reviews the main pathophysiologic and clinical aspects of MODS, with particular attention to the evaluation immunocompetence of the patients.

L-selectin in trauma patients: a marker for organ dysfunction and outcome?

BACKGROUND: Systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS) are important factors affecting morbidity and mortality after trauma. Adhesion molecules, e.g. L-selectin (CD62 L), play crucial roles in both conditions. PATIENTS AND METHODS: In 51 multiple trauma patients, CD62 L surface expression on granulocytes, monocytes, lymphocytes, as well as sCD62 L plasma concentrations were determined during the first 6 days after trauma, starting at the site of accident. Clinical parameters were severity of injury scores (ISS, APACHE II), requirement of red blood cell transfusion, acute lung or liver failure, development of MODS or SIRS, early (< or = 6 d) or late (> 6 d), and outcome. RESULTS: CD62 L expression was reversibly elevated on granulocytes, T cells and monocytes in comparison with initial values. sCD62 L plasma concentrations did not show temporal variations but were depressed throughout observation period, in comparison with healthy controls. Lung failure within the first 6 days was associated with increased CD62 L expression on monocytes and B cells on admission and increased sCD62 L concentrations after 12 and 24 h. Patients with more severe injuries (APACHE II > 20 points) had higher sCD62 L concentrations after 24 h. Non-survivors had decreased sCD62 L (on admission) and T-cell CD62 L expression (after 4 h). Patients with early MODS or SIRS showed increased monocyte CD62 L expression after 6 days. CONCLUSIONS: In multiple trauma patients, severe organ dysfunction is associated with altered CD62 L expression on leukocytes and circulating sCD62 L plasma concentrations. However, the obvious complexity of the pattern currently restricts use of CD62 L quantitation for clinical purposes.

Nitric oxide diffusion across membrane lungs protects platelets during simulated extracorporeal circulation.

BACKGROUND: The absence of a protective endothelial surface on membrane oxygenators during extracorporeal circulation (ECC) promotes platelet trapping and damage, leading to increased bleeding complications. We investigated the effects of transmembranous diffusion of gaseous nitric oxide (NO) on platelets during simulated ECC. MATERIAL AND METHODS: Two paired circuits were run in parallel with fresh, heparinized (1 U mL-1) blood from healthy human donors for 240 min. To one of the paired circuits, 20 ppm NO was added transmembranously. RESULTS: NO significantly attenuated platelet trapping and reduced intracircuit platelet activation evaluated by the release of beta-thromboglobulin, platelet factor 4 and soluble P-selectin. Furthermore, NO significantly preserved platelet reactivity to stimulating agents (ADP and adrenaline), evaluated as the ability to expose P-selectins and activate glycoprotein (GP)-IIb-IIIa. Nevertheless, circulating activated platelets expressing P-selectin or activated GPIIb-IIIa were not different and were not significantly increased. The mean fluorescence intensity of GPIb and GPIIb-IIIa decreased in both circuits equally. CONCLUSIONS: Transmembranous diffusion of gaseous NO revealed protective effects on platelets by reducing thrombocytopenia/pathia and preserving platelet reactivity.

Nitric oxide inhibits tissue factor synthesis, expression and activity in human monocytes by prior formation of peroxynitrite.

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.

Extracorporeal membrane oxygenation for transport of hypoxaemic patients with severe ARDS.

Conventional inter-hospital transfer of patients with severe acute respiratory distress syndrome (ARDS) in need of extracorporeal membrane oxygenation (ECMO) may be risky and in severe hypoxaemic patients may be associated with cerebral hypoxia and death. Therefore, we began a phase 1 study to evaluate the feasibility, complications and outcome of inter-hospital transport of these patients using veno-venous ECMO. Eight patients with severe ARDS and a PaO2/FIO2 < 6.7 kPa at a PEEP > or = 10 cm H2O were placed on a mobile ECMO at the referring hospital. The 495 (SD 123) km inter-hospital transport via a special ground ambulance took 341 (151) min. After transfer, blood-gas tensions were improved in spite of less optimal ventilator settings, compared with data before the start of ECMO. No significant complications occurred. Six patients survived and were discharged from hospital; two patients died because of multiple organ failure. We conclude that initiation of ECMO in hypoxaemic patients before inter-hospital transfer is feasible and enables safe transport to an ECMO centre.

Global and extended coagulation monitoring during extracorporeal lung assist with heparin-coated systems in ARDS patients.

Heparin-coated systems for extracorporeal lung-assist (ECLA) were developed to reduce hemorrhagic risk by lowering the systemic heparinization, monitored by global tests, e.g. activated coagulation time (ACT) and activated partial thromboplastin time (APTT). Since this strategy gives no insight into procoagulant states, five ARDS patients receiving ECLA with heparin-coated systems were investivated for changes in coagulation using both global and extended tests. During ECLA onset the APTT and ACT were within or near normal ranges, platelets decreased 76.5% within 48 h, fibrinogen decreased 28.7%, thrombin-antithrombin-III complexes were elevated before ECLA (53 micrograms/L), but demonstrated an additional peak (238 micrograms/L), plasminogen-activator-inhibitor-1 increased 12-fold, and the C1-inhibitor dropped 14.1%. In conclusion, after the onset of ECLA from a previous prethrombotic state, the precoagulant, anticoagulant, fibrinolytic and complement systems were activated in a similar way to that reported for non-heparinized systems with high-dose heparin. This was however only monitored by an extended test panel which was unable to predict thromboembolic events during ECLA.

The effects of nitric oxide (NO) on platelet membrane receptor expression during activation with human alpha-thrombin.

Nitric oxide (NO) is known as a regulator of platelet function by its anti-adhesive, anti-aggregating, and disaggregating properties. We investigated the modulating effects of the NO-releasing compound SIN-1 (3-morpholino-sydnonimine) on platelet surface glycoprotein (GP) expression during stimulation with human alpha-thrombin. Analysis was performed with two-color flow cytometry using fluoresceine-isothiocyanate (FITC) and phycoerythrin-(PE)-conjugated monoclonal antibodies (MoAbs) directed against GPIb CD42b), GP IIb-IIIa (CD41), P-selectin (CD62P), and MoAb PAC-1 directed against activated GP IIb-IIIa. Preincubation of platelets with SIN-1 (IC50: 1 microM) significantly decreased expression of both total and activated GP IIb-IIIa, and P-selectin in platelets stimulated with thrombin (ED50: 0.05 U/ml), whereas thrombin-induced downregulation of GP Ib was not attenuated. P-selectin expression increased in thrombin-stimulated platelets over time; in contrast, activated GP-IIb-IIIa decreased after an initial peak, indicating that thrombin-induced GP IIb-IIIa activation is spontaneously reversible. SIN-1 reduced P-selectin expression only when added before or at the same time as thrombin, whereas conformationally changed GP-IIb-IIIa was significantly reversed at up to 60 minutes after stimulation by SIN-1. In conclusion, NO attenuates activation marker expression in a dose and time dependent manner. GP-IIb-IIIa is highly sensitive to NO which not only prevents receptor activation but also promotes reversal of activated GP IIb-IIIa complex.

Reduction of platelet trapping in membrane oxygenators by transmembraneous application of gaseous nitric oxide.

Bleeding during extracorporeal circulation (ECC) is often induced and/or aggravated by thrombocytopenia due to platelet-trapping in hollow fiber membrane oxygenators (HFMO). Nitric oxide (NO) has platelet anti-aggregating and dis-aggregating properties. In a paired system we tested whether gaseous NO, added to the gas compartment of one of two parallel running heparin-bonded HFMO attenuated platelet-trapping. Platelet consumption was markedly reduced in the NO-treated HFMO. These data strongly indicate that the application of gaseous NO could prove a new therapeutical approach to reduce bleeding during ECC, serving as a new way of preventing platelet loss, thus reducing the need for high systemic heparinization.

Villous adenoma of ampulla of Vater: a case report.

A 56-year-old female patient presented with pain and tenderness over the epigastric region. Endoscopy showed a polypoid mass at the ampulla of Vater. Endoscopic biopsy showed villous adenoma with moderate cellular atypia. Wide excision of the tumor was performed. After resection, histological examination confirmed the tumor to be a villous adenoma of ampulla of Vater. This is a rare neoplasm with an incidence of 0.04-0.12% in postmortem series. A few cases have been reported in the literature, but only two documented in the Chinese literature to date. Wide excision has had good results and should be regarded as the treatment of choice for benign lesions.

Extracorporeal membrane oxygenation with heparin-coated systems in a 13-month-old infant with acute hypoxic respiratory failure after correction of tetralogy of Fallot.

Hemorrhagic disorders due to systemic heparinization are frequent during extracorporeal lung support (veno-venous extracorporeal membrane oxygenation: vv-ECMO). The development of heparin-coated systems has reduced the need for high-dose heparinization. Whereas the use of these heparin-coated membrane lungs and tubings has been described in former studies in adults, only few reports exist in children. This case report describes the application of a heparin-coated extracorporeal system for long-term vv-ECMO in a 13-month-old infant suffering from acute hypoxic respiratory failure after correction of tetralogy of Fallot. Only moderately elevated levels of activated clotting time (ACT, 120-160 s) and activated partial thromboplastin time (aPTT, 40-60 s) were necessary to avoid thrombotic events in the extracorporeal system. Thoracotomies were performed twice without bleeding complications by discontinuation of the systemic heparinization. We conclude that the use of heparin-coated membrane lungs in infants may improve the safety of extracorporeal lung support and permits surgical intervention without major risk of bleeding.

Dermatofibrosarcoma protuberans of the hand: a case report.

Dermatofibrosarcoma protuberans is a slowly growing, low-grade sarcoma originating in the dermis and subcutaneous tissue. It generally occurs with equal frequency on the trunk and proximal extremities. Only three cases have been reported to occur on the hand. A case of dermatofibrosarcoma protuberans of the right hand anterior to Guyon's canal is reported, and the literature is reviewed.