Comparative study of prescribing patterns of tigecycline for trial patients versus non-trial patients.

BACKGROUND: Comparing published trial patients and non-trial patients in clinical practice, clinicians often doubt whether critically ill patients are sufficiently represented in randomised clinical trials. PATIENTS AND METHODS: This study evaluated the extent of infection with multidrug-resistant (MDR) pathogens, anti-microbial combination therapy, off-label use and targeted-treatment in trial patients versus non-trial patients. RESULTS: Tigecycline therapy was prescribed for off-label use in more than half of the non-trial patients; 77% of trial patients received study medication as first-line therapy in contrast to 25% of non-trial patients (p<0.001). Tigecycline therapy was targeted for 27% of trial patients versus 73% of non-trial patients (p<0.001). Ninety-six percent of non-trial patients were treated for nosocomial infections compared to 23% of trial patients (p<0.001). In one out of 22 (4.5%) trial patients an ESKAPE pathogen was found, whereas rates of vancomycin- resistant Enterococcus faecium, methicillin-resistant Staphylococcus aureus and extended spectrum-ß lactamase- producing Enterobacteriaceae ranged between 13/165 (8%) and 23/165 (14%) for non-trial patients. CONCLUSION: Tigecycline was used for less critical populations in clinical trials than in clinical practice. Our findings confirm the particular need of potent substances such as tigecycline for critically ill patients.

Patients enrolled in randomised clinical trials are not representative of critically ill patients in clinical practice: observational study focus on tigecycline.

It is being increasingly recognised by clinicians and scientists that participants in randomised clinical trials (RCTs) of antibiotics of last resort do not represent the patients who will later be treated with these drugs. Data on this subject are limited and have not been investigated systematically. This observational study aimed to examine this hypothesis quantitatively, using the example of tigecycline. To evaluate the influence of recruitment, patients eligible for clinical trials were retrospectively compared with ineligible patients regarding baseline and clinical characteristics as well as outcome parameters, e.g. length of hospital stay, intensive care unit (ICU) stay, ventilation and mortality. The clinical characteristics of 187 patients illustrated differences in the nature and severity of disease, co-morbidities and outcome. Eligible and ineligible patients differed in a number of parameters, e.g. median APACHE II score (15.5 vs. 28.0), number of liver transplantations (5% vs. 18%; P=0.048), septic shock (21% vs. 49%; P=0.001), need for mechanical ventilation (30% vs. 79%; P<0.001), mean length of ICU stay (19.3 days vs. 40.7 days) and death (19% vs. 46%; P=0.001). Critically ill patients were under-represented in clinical trials. Moreover, only a minority of patients in clinical practice (13%) were potentially eligible for a pivotal RCT. The disparities likely result from strict exclusion criteria in RCTs and recruitment bias. These data emphasise the importance of including critically ill patients in RCTs of antibiotics against multiresistant bacteria in order to account for those who will later be treated.

Reactive metabolites and AGE-RAGE-mediated inflammation in patients following liver transplantation.

Recent investigations have indicated that reactive metabolites and AGE-RAGE-mediated inflammation might play an important role in the pathogenesis of ischemia-reperfusion injury in liver transplantation. In this observational clinical study, 150 patients were enrolled following liver transplantation from deceased donors. The occurrence of short-term complications within 10 days of transplantation was documented. Blood samples were collected prior to transplantation, immediately after transplantation, and at consecutive time points, for a total of seven days after transplantation. Plasma levels of methylglyoxal were determined using HPLC, whereas plasma levels of L-arginine, asymmetric dimethylarginine, advanced glycation endproducts-carboxylmethyllysine, soluble receptor for advanced glycation endproducts, and total antioxidant capacity were measured by ELISA. Patients following liver transplantation were shown to suffer from increased RAGE-associated inflammation with an AGE load mainly dependent upon reactive carbonyl species-derived AGEs. In contrast, carboxylmethyllysine-derived AGEs were of a minor importance. As assessed by the ratio of L-arginine/asymmetric dimethylarginine, the bioavailability of nitric oxide was shown to be reduced in hepatic IRI, especially in those patients suffering from perfusion disorders following liver transplantation. For the early identification of patients at high risk of perfusion disorders, the implementation of asymmetric dimethylarginine measurements in routine diagnostics following liver transplantation from deceased donors should be taken into consideration.

Cell death biomarkers as early predictors for hepatic dysfunction in patients after orthotopic liver transplantation.

BACKGROUND: Valid prognostic factors for early identification of a complicated course after orthotopic liver transplantation from deceased donors are rare. The aim of this study was to investigate the prognostic value of different cell death biomarkers and inflammatory markers in patients after orthotopic liver transplantation from deceased donors. METHODS: In total, 100 patients were evaluated for short-term complications within 10 days after orthotopic liver transplantation from deceased donors. Blood samples were collected before surgery, immediately after the end of the surgical procedure, and 1 day and 3, 5, and 7 days later. Plasma levels of total keratin 18, keratin 18 fragments, interleukin 6, tumor necrosis factor α, and soluble intercellular adhesion molecule 1 were measured. RESULTS: Total keratin 18 was demonstrated to be favorable in its prognostic value for early identification of a complicated course in comparison to routine markers of liver impairment (e.g., aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase). In contrast, inflammation markers (e.g., interleukin 6, tumor necrosis factor α and soluble intercellular adhesion molecule 1) were unsuitable for predicting early complications after liver transplantation from deceased donors. CONCLUSIONS: For early identification of patients at high risk for complications, the implementation of total keratin 18 measurements in routine diagnostics after orthotopic liver transplantation from deceased donors should be taken into consideration.

Right ventricular function during orthotopic liver transplantation: three-dimensional transesophageal echocardiography and thermodilution.

BACKGROUND: Right ventricular (RV) function is an important aspect of anesthesia management during orthotopic liver transplantation (OLT). Because of its geometrical complexity, assessment of RV dimensions with transesophageal echocardiography (TEE) is a difficult task. The aim of this prospective single-site study was to investigate the feasibility of intraoperative assessment of RV parameters based on reconstructive three-dimensional (3D) TEE and to compare the measurements to thermodilution-derived values acquired with a modified pulmonary artery catheter. MATERIAL/METHODS: Measurements were performed at four different time points during 30 OLT with 3D-TEE. At the same time comparative values of RV parameters were acquired with a fast-response thermistor pulmonary artery catheter. RESULTS: 3D reconstruction was feasible in all patients. RV dimensions measured with 3D-TEE averaged 119.4 ml (± 38.5 ml) for enddiastolic and 68.9 ml (± 27.7 ml) for endsystolic volumes. The RV ejection fraction was 42.2% (± 9.3%). The volumes obtained by thermodilution were 263.7 ml (± 64.5 ml) enddiastolic and 159.3 ml (± 47.5 ml) endsystolic, both significantly greater than by 3D-TEE, and the ejection fraction was found to be 39.5% (± 8.4%). No correlation was found between the volumes or the function determined by either method. CONCLUSIONS: Reconstructive 3D-TEE is a viable technique during OLT and leads to plausible RV parameters. However, no correlation was found with simultaneous measurements or parameters performed with thermodilution. However, based on our data cardiac output measurements by thermodilution appear reasonable. Due to both lack of agreement with 3D-TEE and extraordinary high RV volumes the question about the most valuable monitoring technique of RV dimensions and function during OLT can not finally be answered.

Left ventricular outflow tract: intraoperative measurement and changes caused by mitral valve surgery.

BACKGROUND: The impact of mitral valve surgery on left ventricular outflow tract (LVOT) dimensions is unclear. Real-time three-dimensional transesophageal echocardiography permits excellent visualization of the LVOT and might improve standard two-dimensional measurements. In this study, LVOT area and shape were assessed before and after mitral valve surgery. METHODS: Thirty-five patients undergoing mitral valve repair or replacement were retrospectively included in the study and compared with 15 patients undergoing coronary artery bypass grafting. LVOT area was measured by planimetry. Maximum possible methodologic errors by assuming a circular LVOT and an eccentricity index were calculated. LVOT diameter in a midesophageal long-axis view served to calculate the error for the circular LVOT determined in common intraoperative practice. RESULTS: Common intraoperative two-dimensional measurements underestimated actual LVOT area by 21%. Mitral valve surgery led to a significant reduction of LVOT area by 7%. Although LVOT height remained unchanged, width decreased from 2.72 to 2.53 cm (-7%), resulting in a more circular shape of the LVOT. This effect was more pronounced the smaller the size of the implanted annuloplasty ring or prosthesis. Coronary artery bypass grafting did not affect the LVOT. Left ventricular ejection fraction was significantly correlated with LVOT eccentricity. Impaired ventricular function and higher end-systolic volumes were associated with a rounder shape. CONCLUSIONS: The eccentric LVOT shape leads to a distinct underestimation of its area with two-dimensional measurements. LVOT eccentricity is less distinct in patients with low ejection fractions and higher end-systolic volumes. LVOT width is decreased through annuloplasty rings and prostheses, and the smaller the implanted device, the more profound the reduction.

Redox responses in patients with sepsis: high correlation of thioredoxin-1 and macrophage migration inhibitory factor plasma levels.

Background. Redox active substances (e.g., Thioredoxin-1, Macrophage Migration Inhibitory Factor) seem to be central hubs in the septic inflammatory process. Materials and Methods. Blood samples from patients with severe sepsis or septic shock (n = 15) were collected at the time of sepsis diagnosis (t0), and 24 (t24) and 48 (t48) hours later; samples from healthy volunteers (n = 18) were collected once; samples from postoperative patients (n = 28) were taken one time immediately after surgery. In all patients, we measured plasma levels of IL-6, TRX1 and MIF. Results. The plasma levels of MIF and TRX1 were significantly elevated in patients with severe sepsis or septic shock. Furthermore, TRX1 and MIF plasma levels showed a strong correlation (t0: r(sp) = 0.720, ρ = 0.698/t24: r(sp) = 0.771, ρ = 0.949). Conclusions. Proinflammatory/~oxidative and anti-inflammatory/~oxidative agents show a high correlation in order to maintain a redox homeostasis and to avoid the harmful effects of an excessive inflammatory/oxidative response.

Effects of ketamine on hypoxic pulmonary vasoconstriction in the isolated perfused lungs of endotoxaemic mice.

BACKGROUND AND OBJECTIVE: During sepsis and endotoxaemia, hypoxic pulmonary vasoconstriction (HPV) is impaired. Sedation of septic patients in ICUs is performed with various anaesthetics, most of which have pulmonary dilatory properties. Ketamine is a sympathetic nervous system-activating anaesthetic that preserves cardiovascular stability. The effects of ketamine on the pulmonary vasculature and HPV during sepsis have not been characterized yet. METHODS: Therefore, isolated lungs of mice were perfused with ketamine (0, 0.1, 1.0, and 10 mg kg(-1) body weight min) 18 h following intraperitoneal injection of lipopolysaccharide (LPS); untreated mouse groups served as controls (n = 7 per group, respectively). Pulmonary artery pressure (PAP) and pressure-flow curves during normoxic (FiO(2) = 0.21) and hypoxic (FiO(2) = 0.01) ventilation were obtained. RESULTS: HPV was reduced in endotoxaemic animals when compared with controls (means +/- SD; DeltaPAP control 103 +/- 28% vs. LPS 23 +/- 25%, P < 0.05). Ketamine caused a dose-dependent reduction of HPV in the lungs of control (DeltaPAP 0 mg kg(-1) min(-1) ketamine 103 +/- 28% vs. 10 mg kg(-1) min(-1) ketamine 28 +/- 21%, P < 0.05) and septic animals (DeltaPAP 0 mg kg(-1) min(-1) ketamine 23 +/- 25% vs. 10 mg kg(-1) min(-1) ketamine 0 +/- 4%, P < 0.05). Analysis of pressure-flow curves revealed that ketamine partly reversed the endotoxin-induced changes in basal pulmonary vascular wall properties rather than interfering with the HPV response itself. CONCLUSION: Ketamine modified baseline pulmonary vascular properties, resulting in a reduced HPV responsiveness in untreated mice. Further, ketamine counteracted the LPS-induced changes in pulmonary vascular pressure-flow relationships, but did not affect impaired HPV in this murine endotoxaemia model.

Role of endogenous nitric oxide in endotoxin-induced alteration of hypoxic pulmonary vasoconstriction in mice.

Pulmonary vasoconstriction in response to alveolar hypoxia (HPV) is frequently impaired in patients with sepsis or acute respiratory distress syndrome or in animal models of endotoxemia. Pulmonary vasodilation due to overproduction of nitric oxide (NO) by NO synthase 2 (NOS2) may be responsible for this impaired HPV after administration of endotoxin (LPS). We investigated the effects of acute nonspecific (N(G)-nitro-L-arginine methyl ester, L-NAME) and NOS2-specific [L-N6-(1-iminoethyl)lysine, L-NIL] NOS inhibition and congenital deficiency of NOS2 on impaired HPV during endotoxemia. The pulmonary vasoconstrictor response and pulmonary vascular pressure-flow (P-Q) relationship during normoxia and hypoxia were studied in isolated, perfused, and ventilated lungs from LPS-pretreated and untreated wild-type and NOS2-deficient mice with and without L-NAME or L-NIL added to the perfusate. Compared with lungs from untreated mice, lungs from LPS-challenged wild-type mice constricted less in response to hypoxia (69 +/- 17 vs. 3 +/- 7%, respectively, P < 0.001). Perfusion with L-NAME or L-NIL restored this blunted HPV response only in part. In contrast, LPS administration did not impair the vasoconstrictor response to hypoxia in NOS2-deficient mice. Analysis of the pulmonary vascular P-Q relationship suggested that the HPV response may consist of different components that are specifically NOS isoform modulated in untreated and LPS-treated mice. These results demonstrate in a murine model of endotoxemia that NOS2-derived NO production is critical for LPS-mediated development of impaired HPV. Furthermore, impaired HPV during endotoxemia may be at least in part mediated by mechanisms other than simply pulmonary vasodilation by NOS2-derived NO overproduction.