[Awake ECMO therapy in airway stenosis. Bronchoscopic treatment using laser resection]. / Wach-ECMO-Therapie bei Atemwegsstenose. Bronchoskopische Behandlung mithilfe der Laserresektion.

This article presents the case of a 62-year-old patient with cancer in the left upper pulmonary lobe who underwent lobe resection with postoperative respiratory insufficiency. The right upper lobe had already been resected 5 years earlier because of an adenocarcinoma. Prior to the present surgery a computed tomography scan detected a narrow stenosis at the former resection site; however, both pulmonary lobes beyond this stenosis appeared to be sufficiently ventilated. After resection of the left upper lobe attempted extubation was unsuccessful due to insufficient global gas exchange as the stenosis prevented ventilation of the right lung. Bronchoscopy provided evidence of a normal diameter of the bronchus behind the stenosis so both lobes were to be recruited after possible correction of this section. A veno-venous extracorporeal membrane oxygenation device (ECMO) was established as bridging therapy to attain normal gas exchange. As the patient showed no muscle weakness and was cooperative, extubation was performed and spontaneous breathing occurred without any support while still under ECMO treatment. The stenosis was reduced by bronchoscopic laser resection within seven consecutive sessions. Each of these surgeries was conducted with the patient under general anesthesia with oral intubation and jet ventilation in combination with the ECMO. The patient was extubated after each treatment session and weaned from ECMO after the final resection within 2 days. This case demonstrates the use of ECMO in combination with surgical procedures in a spontaneously breathing patient as a causal therapy and option for selected patients to prevent complications from long-term ventilation.

Role of glutamine administration on T-cell derived inflammatory response after cardiopulmonary bypass.

BACKGROUND & AIMS: Cardiac surgery provokes an inflammatory response for which the endothelium, the myocardium, and monocytes/macrophages are primarily responsible. T cells are altered in a different way whereby the pro-inflammatory pathway is suppressed. From the results of experimental studies it was concluded that glutamine (Gln) enhances the production of T-cell cytokines in conditions of Gln deprivation. The aim of this clinical study was to evaluate the role of a perioperative Gln infusion on intracellular inflammatory T-cell cytokine expression in patients undergoing elective cardiac surgery and to evaluate the effects on systemic inflammation, organ dysfunction and ICU length of stay. METHODS: In this prospective, randomized, double-blind study, we included 78 patients (age level older than 70 years, ejection fraction less than 40%, or mitral valve replacement) undergoing elective cardiosurgery with cardiopulmonary bypass. We randomly assigned each subject to receive an infusion with either Gln (0.5 g/kg/day, group A) or an isonitrogenous, isocaloric, isovolemic nutritional solution (group B) or physiological NaCl 0.9% (group C, to eliminate an unspecific nutritional effect). We started the infusion after the induction of anesthesia with 1000 ml/24 h and maintained this state for 3 days. RESULTS: On the first postoperative day plasma Gln levels in group A were significantly increased (958 +/- 331 microM) compared to group B (527 +/- 105 microM) and group C (489 +/- 104 microM), and remained higher until the third postoperative day. At the beginning and after surgery intracellular interleukin (IL)-1, IL-6, IL-8, and tumor necrosis factor-alpha levels in T cells showed no differences between the groups. Also, no differences could be observed with regard to C-reactive protein, SOFA score, heart and circulation support, postoperative ventilation time, and ICU length of stay. CONCLUSIONS: The elevation of Gln plasma levels as a result of 0.5 g/kg/day perioperative Gln infusion has no influence on the T-cell derived inflammatory response, indicating a sufficient supply of Gln. A Gln supplementation in cardiac surgery patients without a clear Gln deficiency seems not to affect the intracellular inflammatory T-cell cytokine expression.

Perioperative application of L-alanyl-L-glutamine in cardiac surgery: effect on the polarized T cell cytokine expression.

At risk patients undergoing cardiac surgery with cardiopulmonary bypass have increased rates of postoperative infectious morbidity. Postoperatively, after cardiac surgery, an immunosuppression in the form of a polarization of T helper (Th) cells with a decreased Th1 response (IL-2 and IFN-gamma) and an increased Th2 response (IL-4 and IL-10) is recognized. Therapeutic strategies to modulate the immunological response include special key nutrients such as the amino acid glutamine favoring the Th2 response. There is no information available concerning its effect in patients undergoing cardiac surgery. The aim of this clinical study was to evaluate the effects of a perioperative infusion of glutamine on the polarized lymphocyte T cell cytokine expression and on infectious morbidity in cardiac surgery patients at risk of infection. Seventy-eight patients were included in the study undergoing elective cardiac surgery with a lymphopenia less than 1.2 giga/l. One or more of the following criteria had to be met: age older than 70 years, ejection fraction less than 40%, or mitral valve replacement. We randomly assigned patients to receive infusions of either high-dose L-alanyl-L-glutamine dipeptide [0.5 g/(kg day) glutamine] dissolved in an amino acid solution or an isonitrogeneous, isocaloric, isovolemic nutritional solution. An additional group with normal saline served as control to eliminate any nonspecific nutritional effect. We started the infusion after induction of anesthesia with 1,000 ml/24 h and continued it for 3 days. The primary endpoint was intracellular T cell cytokine expression (including the description in tertiles) on the first postoperative day (pod 1). Secondary endpoints were postoperative infection rate, mortality rate, cardiovascular circulation ventilation time, and renal function. A high-dose perioperative glutamine application leading to mean plasma levels of 1,177 microM had only a minor influence on the polarized intracellular T cell cytokine expression. On pod 1 there was a polarization of T cells, i.e., an augmented Th2 response with an increased number of IL-6 and IL-10 producing cells. On the other side the Th1 response with IL-2 and TNF-alpha declined on pods 1 and 2. Only the intracellular IL-2 response in the lower tertile of IL-2 production was improved with glutamine indicating a small influence. We did not observe any effects on the numbers of postoperative infections; on mortality rate; on cardiovascular circulation; on ventilation time or on renal function. The elevation of glutamine plasma levels by a perioperative intravenous infusion of L-alanyl-L-glutamine influenced the intracellular expression of IL-2 in the lower tertile only slightly. However, mean glutamine values in the other groups remained above or close 500 microM, thus suggesting that glutamine supply to the immune cells was still adequate in most patients, and that glutamine deficiency, if it occurred, was marginal. In the event of a severe glutamine deficiency the observed effect on cytokine production could be more pronounced. Furthermore, we could not observe any obvious clinical advantage in this at risk cardiac surgical patient population. A glutamine supplementation for patients undergoing cardiac surgery without a clear glutamine deficiency is not recommended.

Intracellular alpha-keto acid quantification by fluorescence-HPLC.

Procedures for the analysis of free alpha-keto acids in human fluids (i.e. plasma, cerebrospinal fluid, urine, etc.) as well as for studying the dynamic free alpha-keto acid pools in differentiated tissues and organ cells have been the subject of growing clinical interest in the study of metabolic regulatory and pathophysiological phenomena. Due to the high instability and polarity of the alpha-keto acids being examined, the development of a quantitative and reproducible analysis of metabolically relevant intracellular alpha-keto acids still presents a substantial methodological challenge. The aim of small sample size, rapid, non-damaging and "metabolism-neutral" cell isolation, careful sample preparation and stability, as well as reproducible analytics technology is not often achieved. Only few of the methods described can satisfy the rigorous demands for an ultra-sensitive, comprehensive and rapid intracellular alpha-keto acid analysis.

[Successful thrombolysis of a massive pulmonary embolism following pneumonectomy]. / Erfolgreiche Thrombolyse einer massiven Lungenembolie nach Pneumektomie.

Pulmonary embolism is a rare but life-threatening complication after major lung surgery. The case of a patient with sudden onset of hemodynamic instability 2 days after right-sided pneumonectomy is reported. After finding massive right ventricular dysfunction by transthoracic echocardiography and detection of an embolism by computed tomography, a successful and uneventful thrombolysis was performed. The risks and benefits of this procedure are discussed with reference to the literature.

Pathways involved in alanyl-glutamine-induced changes in neutrophil amino- and alpha-keto acid homeostasis or immunocompetence.

We examined the effects of DON [glutamine-analogue and inhibitor of glutamine-requiring enzymes], alanyl-glutamine (regarding its role in neutrophil immunonutrition) and alanyl-glutamine combined with L-NAME, SNAP, DON, beta-alanine and DFMO on neutrophil amino and alpha-keto acid concentrations or important neutrophil immune functions in order to establish whether an inhibitor of *NO-synthase [L-NAME], an *NO donor [SNAP], an analogue of taurine and a taurine transport antagonist [beta-alanine], an inhibitor of ornithine-decarboxylase [DFMO] as well as DON could influence any of the alanyl-glutamine-induced effects. In summary, irrespective of which pharmacological, metabolism-inhibiting or receptor-mediated mechanisms were involved, our results showed that impairment of granulocytic glutamine uptake, modulation of intracellular glutamine metabolisation and/or de novo synthesis as well as a blockade of important glutamine-dependent metabolic processes may led to significant modifications of physiological and immunological functions of the affected cells.

Nitric oxide and polyamine pathway-dependent modulation of neutrophil free amino- and alpha-keto acid profiles or host defense capability.

We have examined the effects of N(omega)-nitro-L-arginine-methylester-hydrochloride [L-NAME; inhibitor of nitric oxide synthase], S-nitroso-N-acetyl-penicillamine [SNAP; nitric oxide donor], alpha-difluoro-methyl-ornithine [DFMO; inhibitor of ornithine decarboxylase] arginine or ornithine as well as the combination of arginine or ornithine with L-NAME, SNAP or DFMO on intracellular free amino- and alpha-keto acid profiles and the immune function markers superoxide anion and hydrogen peroxide generation as well as released myeloperoxidase activity in neutrophils (PMN). Although the underlying mechanisms still remain unclear, we believe from our results that nitric oxide as well as polyamine-dependent pathways are involved in the signal transmission of free radical molecule, beneficial nutritional therapy or maleficient pharmacological stress-induced alterations in PMN nutrient composition. Relevant changes in intragranulocyte free amino- and alpha-keto acid homeostasis and metabolism, especially, may be one of the determinants in PMN nutrition that positively or negatively influences and modulate neutrophil host defence capability and immunocompetence.

Relationship of taurine and other amino acids in plasma and in neutrophils of septic trauma patients.

Recently, an interdependency of plasma taurine and other amino acids as well as metabolic and clinical variables implicating therapeutic options was reported. This result may be an indication that plasma taurine levels are directly related to intracellular levels. Therefore, the aim of this study was to analyse the possible relationship between taurine levels in plasma and in neutrophils, the relationship to other amino acids, and variables quantifying metabolic impairment and severity of sepsis in multiple trauma patients developing sepsis. After multiple trauma taurine decreased significantly in plasma in thirty-two patients as well as within the neutrophil and does not recover in sepsis. Lower individual levels in the neutrophil did not follow lower individual levels in plasma and no correlation of taurine in plasma and in the neutrophils could be observed. In sepsis, only plasma showed an interdependency of taurine, aspartate, and glutamate. No association between taurine plasma or intracellular levels and SOFA score as indicator for severity of sepsis or metabolic variables was observed. After multiple trauma and in sepsis, taurine uptake in cells (which is regulated in different ways), and intracellular taurine (which serves e.g. as an osmolyte) can be influenced. Therefore a prediction of the neutrophil taurine pool seems not fully possible from taurine plasma levels. Intracellular taurine has some unique properties explaining the missing interdependency despite some similarities in osmoregulation and metabolic interactions to other amino acids. The association of taurine, aspartate, and glutamate in plasma cannot be simply transferred to the neutrophils intracellular level. The clinical meaning of the plasma correlation remains unclear. A dependency of plasma and neutrophil taurine to severity of sepsis and to metabolic variables seems not possible because of the multifactorial pathophysiology of sepsis.

Alterations in neutrophil (PMN) free intracellular alpha-keto acid profiles and immune functions induced by L-alanyl-L-glutamine, arginine or taurine.

The objective of this study was to determine the dose as well as duration of exposure-dependent effects of L-alanyl-L-glutamine, arginine or taurine on polymorphonuclear neutrophil (PMN) free alpha-keto acid profiles and, in a parallel study, on PMN immune functions. Exogenous L-alanyl-L-glutamine significantly increased PMN alpha-ketoglutarate, pyruvate PMN superoxide anion (O2-) generation, hydrogen peroxide (H2O2) formation and released myeloperoxidase (MPO) activity. Arginine also led to significant increases in alpha-ketoglutarate, pyruvate, MPO release and H2O2 generation. Formation of O2- on the other hand was decreased by arginine. Incubation with taurine resulted in lower intracellular pyruvate and alpha-ketobutyrate levels, decreased O2- and H2O2 formation and a concomitant significantly increased MPO activity. We therefore believe that considerable changes in PMN free-alpha-keto-acid profiles, induced for example by L-alanyl-L-glutamine, arginine or taurine, may be one of the determinants in cell nutrition that considerably modulates the immunological competence of PMN.

Benzodiazepine receptor-dependent modulation of neutrophil (PMN) free amino- and alpha-keto acid profiles or immune functions.

We have examined the effects of midazolam, Ro 5-4864 (agonist for "peripheral" [p] benzodiazepine receptors [BR]), PK 11195 (antagonist for pBR), flumazenil (antagonist for "central" BR), naloxone (antagonist for opiate receptors) and the combination of midazolam and Ro 5-4864, PK 11195, flumazenil or naloxone on intracellular amino- and alpha-keto acids and the immune function markers superoxide anion (O(2)(-)), hydrogen peroxide (H(2)O(2)) and released myeloperoxidase (MPO) activity in neutrophils (PMN). Only midazolam and Ro 5-4864 led to significant changes in the dynamic PMN free amino- and alpha-keto acid pools. Concerning PMN immune function markers, midazolam and Ro 5-4864 significantly decreased O(2)(-) and H(2)O(2) formation and released MPO. When midazolam and Ro 5-4864 were applied together they appeared to act additively. Pre-incubation with PK 11195 partially neutralized the midazolam effects whereas flumazenil or naloxone showed no effects. We therefore believe that pBR are involved in the signal transmission of anesthetic-induced cellular metabolic changes in PMN.

Effects of ornithine on neutrophil (PMN) free amino acid and alpha-keto acid profiles and immune functions in vitro.

The objective of this study was to determine the effects of ornithine on polymorphonuclear leucocyte (PMN) free amino- and alpha-keto acid profiles, superoxide anion (O2-) generation, hydrogen peroxide (H2O2) formation and released myeloperoxidase activity (MPO). Exogenous ornithine significantly increased PMN asparagine, glutamine, aspartate, glutamate, arginine, citrulline, alanine, alpha-ketoglutarate and pyruvate as intracellular ornithine increased. Concerning PMN immune function markers ornithine increased H2O2-generation and MPO activity while O2- -formation was decreased. We believe therefore that ornithine is important for affecting PMN "susceptible free amino- and alpha-keto acid pool" although the mechanisms are not yet clear. This may be one of the determinants in PMN nutrition considerably influencing and modulating PMN host defense capability.

Efficacy and Safety of the Platelet-Activating Factor Receptor Antagonist BN 52021 (Ginkgolide B) in Patients with Severe Sepsis : A Randomised, Double-Blind, Placebo-Controlled, Multicentre Trial.

OBJECTIVE: To evaluate the efficacy and safety of the natural platelet-activating factor receptor antagonist, BN 52021 (ginkgolide B) in the treatment of patients with severe sepsis related to Gram-negative and mixed bacterial infection. DESIGN AND SETTING: Prospective, randomised, double-blind, placebo-controlled, multicentre study carried out in 13 academic medical intensive care centres in Germany with up to 14 patients per centre. PATIENTS: 88 patients with severe sepsis under standard medical and surgical care: nine patients with pure Gram-positive infection, 79 patients with Gram-negative or mixed bacterial infections (subgroup for which efficacy was to be established). INTERVENTIONS: Patients were randomised to receive either placebo or BN 52021 1.25 mg/kg bodyweight intravenously every 12h over a 4-day period in addition to their standard medical and surgical care. MAIN OUTCOME MEASURES AND RESULTS: The primary efficacy variable was the 28-day all-cause mortality rate. The treatment groups were similar with respect to demographic data and prognostic factors influencing the outcome except for bodyweight and adequacy of antibiotic therapy. Analysis of patients with Gram-negative or mixed bacterial infection, for which efficacy was to be established, resulted in a 28-day all-cause mortality of 42.5% in the placebo group (n = 40; 17 deaths) versus 38.5% in the BN 52021 group (n = 39; 15 deaths). Among all randomised patients, the 28-day all-cause mortality rate was 40.9% in the placebo group (n = 44; 18 deaths) and 38.6% in the BN 52021 group (n = 44; 17 deaths). There were no differences in frequency and severity of adverse events between the two treatment groups. CONCLUSIONS: Four-day administration of BN 52021 failed to demonstrate a statistically significant reduction in mortality in patients with severe sepsis suspected or confirmed to be related to infections other than Gram-positive bacterial infection.

[Small pox--infection, therapy and anaesthesiological management (part 1)]. / Pocken--Klinik, Therapie und anästhesiologische Aspekte (Teil 1).

Smallpox is an acute contagious and sometimes fatal infectious disease. It is caused by the variola-virus. Smallpox is characterized by a typical disease form with a progressive distinctive skin rash, especially at face, arms and legs. Smallpox has a fatality rate of about 30 % and the therapy of infected patients is only symptomatically. As prevention the WHO initiated worldwide vaccination programs in the year 1967. The last naturally occurring case of smallpox in the world was in Somalia in 1977. Since then the only known cases of smallpox happened from an outbreak in Birmingham, England caused by a laboratory accident in the year of 1979. On May the 8 th 1980 the disease was declared as eliminated from the world by the WHO (WHO-Resolution 33.33). A natural occurrence of the variola-virus seems to be not given. Nevertheless the virus exists for research in two laboratories, the American Centers of Disease Control and Prevention in Atlanta, Georgia and in the Russian Research Center for Virology and Biotechnics in Kolzowo, Sibiria. Threatening infections with smallpox or other microorganisms, used as bioweapons, get a new dimension through global terrorism. The variola-virus represents an optimal candidate for bioweapons. It is easy to replicate, it is highly contagious and the transmission over aerosol or direct contact from man to man is easy to handle. After the disease was eliminated from the world, routine vaccination among general public was stopped. Therefore younger people don't possess any vaccination protection. Older formerly vaccinated people probably have only a non-sufficient protection. Because of the smallpox elimination a lot of physicians have no experience with this disease. An outbreak of this smallpox isn't only controlled by new vaccination. In our times we need adapted prevention-standards, pox-alarm plans and quarantine standards.

Low plasma glutamine after multiple trauma: relationship with intracellular glutamine in polymorphonuclear neutrophils during prolonged ICU stay.

BACKGROUND: Aim of the study was to evaluate whether low plasma glutamine (GLN) is related to low intracellular GLN in stress-affected cells such as polymorphonuclear neutrophil (PMN). We hypothesized, that because low plasma GLN is assumed to have an impact on clinical outcome, stress-affected cells may also show low GLN contents. METHODS: Thirty-nine consecutive severely injured trauma patients staying at least 10 days at a surgical intensive care unit (ICU) of a university hospital were separated into two groups: group one (n = 16) with low plasma GLN (< 420 micromol/l in average during ICU stay), and group two (n = 23) with normal plasma GLN. Initial blood samples for GLN analyses were collected within 24 h of admission at ICU. Further blood samples were taken on days 5 and 10 at 08:00 hours. RESULTS: Patients in both groups showed no differences regarding demographic data, surgical interventions or infections. Acute physiology and chronic health evaluation (APACHE) II and the sequential organ failure assessment (SOFA) score and mortality rate were also comparable. During the study period, intracellular PMN GLN contents and concentrations did not differ between both groups. On the first day, intracellular PMN GLN content in the low plasma GLN group peaked at 5.01 +/- 3.06 x 10(-16) mol and in normal plasma GLN group at 4.73 +/- 2.57 x 10(-16) mol above the level of healthy individuals. In both groups, content decreased significantly towards the end of the observation period (group one: 2.79 +/- 1.59 x 10(-16) mol and group two: 2.63 +/- 1.71 x 10(-16) mol). A correspondent course could be observed for cell volumes. In contrast, variation of intracellular GLN concentrations remained within the reference range throughout the observation period: group one 836 +/- 510 micromol/l on day 1 and 582 +/- 331 micromol/l on day 10, and group two 788 +/- 428 micromol/l on day 1 and 548 +/- 356 micromol/l on day 10. No correlation between plasma GLN and intracellular GLN was found in either group. CONCLUSION: No association between low plasma GLN and low intracellular GLN in PMN was found in a cohort of severely injured trauma patients with a minimum stay of 10 days at ICU.

Enteral nutrition practice in a surgical intensive care unit: what proportion of energy expenditure is delivered enterally?

The object of this study was to document enteral feeding practice in critically ill patients in a surgical intensive care unit. We asked what proportion of measured energy expenditure is delivered enterally. Patient, material, and therapy-related factors should be assessed and related to enteral nutrition. Sixty patients receiving enteral nutrition for a period of at least 10 days were included in the study. Mean daily energy expenditure was 27.8+8.7 kcal/kg. Mean daily enteral delivered calories reached 19.7+/-10.3 kcal/kg (P<0.05). Twenty-one out of 60 (35%) patients were fed isocalorically; 46% of enteral nutrition days failed to reach 80% of energy expenditure. Ten out of 30 patients (33%) fed over a gastric tube were nourished isocalorically in comparison to 8 out of 20 patients (40%) fed over a duodenal tube. Factors associated with hypocaloric enteral feeding in multiple logistic regression were abdominal, pelvic and lumbal spine trauma, gastrointestinal intolerance, problems with the feeding tube, additional surgical interventions, airway management and use of fentanyl. In the course of the study, gastrointestinal complications were the cause for more than 50% of insufficient enteral delivery cases, while therapy and material related reasons contribute to only a minor part.Abdominal, pelvic and lumbal spine traumas are associated with a higher possibility towards developing problems with enteral delivery, as shown by odds-ratios greater than eight. These diagnoses amounted in our investigation to nearly 40% and make a great difference to medical patients. Therefore, recommendations for optimising enteral feeding must take the concerned patient collective into account.

Randomized, placebo-controlled trial of the anti-tumor necrosis factor antibody fragment afelimomab in hyperinflammatory response during severe sepsis: The RAMSES Study.

OBJECTIVE: This study investigated whether treatment with the anti-tumor necrosis factor-alpha monoclonal antibody afelimomab would improve survival in septic patients with serum interleukin (IL)-6 concentrations of >1000 pg/mL. DESIGN: Multicenter, double-blind, randomized, placebo-controlled study. SETTING: Eighty-four intensive care units in academic medical centers in Europe and Israel. PATIENTS: A total of 944 septic patients were screened and stratified by the results of a rapid qualitative immunostrip test for serum IL-6 concentrations. Patients with a positive test kit result indicating IL-6 concentrations of >1000 pg/mL were randomized to receive either afelimomab (n = 224) or placebo (n = 222). Patients with a negative IL-6 test (n = 498) were not randomized and were followed up for 28 days. INTERVENTIONS: Treatment consisted of 15-min infusions of 1 mg/kg afelimomab or matching placebo every 8 hrs for 3 days. Standard surgical and intensive care therapy was otherwise delivered. MEASUREMENTS AND MAIN RESULTS: The study was terminated prematurely after an interim analysis estimated that the primary efficacy end points would not be met. The 28-day mortality rate in the nonrandomized patients (39.6%, 197 of 498) was significantly lower (p <.001) than that found in the randomized patients (55.8%, 249 of 446). The mortality rates in the IL-6 test kit positive patients randomized to afelimomab and placebo were similar, 54.0% (121 of 224) vs. 57.7% (128 of 222), respectively. Treatment with afelimomab was not associated with any particular adverse events. CONCLUSIONS: The IL-6 immunostrip test identified two distinct sepsis populations with significantly different mortality rates. A small (3.7%) absolute reduction in mortality rate was found in the afelimomab-treated patients. The treatment difference did not reach statistical significance.

Plasminogen-activator-inhibitor-1 4G/5G promoter polymorphism and prognosis of severely injured patients.

A single base pair insertion/deletion (4G/SG) promoter polymorphism in the plasminogen-activator-inhibitor-1 (PAI-1) gene is thought to play a part in prognosis after severe trauma. We investigated the relation between outcome of severe trauma, PAI-1 concentrations, and PAP-1 genotype in 61 patients who had been severely injured. 11 (58%) of 19 patients with genotype 4G/4G did not survive, whereas only eight (28%) of 29 patients with heterozygous genotype 4G/SG, and two (15%) of 13 patients with genotype 5G/5G died. The PAI-1 4G allele is associated with high concentrations of PAI-1 in plasma and a poor survival rate after severe trauma.