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Byline: Nicolas Boussekey (1), Arnaud Chiche (2), Karine Faure (4), Patrick Devos (3), Benoit Guery (4), Thibaud d'Escrivan (2), Hugues Georges (2), Olivier Leroy (2) Keywords: High volume hemofiltration; Septic shock; Acute renal failure; Vasopressor; Randomized study Abstract: Objective High volume hemofiltration (HVHF) has shown potential benefits in septic animals and a few reports suggested a hemodynamic improvement in humans. However, randomized studies are still lacking. Our goal was to evaluate the hemodynamic effects of HVHF in septic shock patients with acute renal failure (ARF). Design and setting Prospective randomized study in an intensive care unit (ICU). Patients Twenty patients with septic shock and ARF. Interventions Patients were randomized to either high volume hemofiltration [HVHF 65 ml/(kg h)] or low volume hemofiltration [LVHF 35 ml/(kg h). Vasopressor dose was adjusted to reach a mean arterial pressure (MAP) > 65 mmHg. Measurements and results We performed six hourly measurements of MAP, norepinephrine dose, PaO.sub.2/FiO.sub.2 and lactate, and four daily urine output and logistic organ dysfunction (LOD) score. Baseline characteristics of the two groups were comparable on randomization. Mean norepinephrine dose decreased more rapidly after 24 h of HVHF treatment compared to LVHF treatment (P = 0.004) whereas lactate and PaO.sub.2/FiO.sub.2 did not differ between the two treatment groups. During the 4-day follow-up, urine output was slightly increased in the HVHF group (P = 0.059) but the LOD score evolution was not different. Duration of mechanical ventilation, renal replacement therapy and ICU length of stay were also comparable. Survival on day 28 was not affected. Conclusion HVHF decreased vasopressor requirement and tended to increase urine output in septic shock patients with renal failure. However, a larger trial is required to confirm our results and perhaps to show a benefit in survival. Author Affiliation: (1) Intensive Care and Infectious Disease Unit, Tourcoing Hospital, 135, rue du President Coty, BP 619, 59208, Tourcoing cedex, France (2) Intensive Care and Infectious Disease Unit, Tourcoing Hospital, University of Lille II, Lille, France (3) Department of Biostatistics, University of Lille II, Lille, France (4) Infectious Diseases Unit, CHRU Lille, University of Lille II, Lille, France Article History: Registration Date: 11/04/2008 Received Date: 04/10/2007 Accepted Date: 02/04/2008 Online Date: 30/04/2008

Byline: Jens C. Kubitz (1), Stefanie Forkl (2,3), Thorsten Annecke (3), Nils Kronas (2,3), Alwin E. Goetz (1), Daniel A. Reuter (1) Keywords: Systolic pressure variation; Pulse pressure variation; Fluid responsiveness; Cardiac afterload; Vasopressor; Heart--lung interactions Abstract: Objective This study was performed to investigate the effect of vasopressor therapy on systolic pressure variation (SPV) and pulse pressure variation (PPV) compared to experimentally measured left ventricular stroke volume variation (SVV). Design and setting Prospective study in a university laboratory. Subjects Twelve anesthetized and mechanically ventilated pigs. Interventions Increase in mean arterial pressure (by 100%) using phenylephrine and decrease (by 38%) using adenosine. Measurements and results SPV and PPV were calculated and compared to SVV derived from aortic blood flow measurements. SPV was significantly affected by changes in arterial pressure [4.6% (1.5) vs. 6.3% (2.1), pa- Conclusion For guiding fluid therapy in patients under vasopressor support, PPV seems superior to SPV. Author Affiliation: (1) Department of Anesthesiology, University of Hamburg, Hamburg-Eppendorf University Hospital, 20246, Hamburg, Germany (2) Institute for Surgical Research, University of Munich, Munich, Germany (3) Department of Anesthesiology, University of Munich, Grosshadern University Hospital, Munich, Germany Article History: Registration Date: 27/03/2008 Received Date: 22/11/2007 Accepted Date: 24/03/2008 Online Date: 22/04/2008 Article note: Conflicts of interest: AEG and DAR are members of the medical advisory board of Pulsion Medical Systems.

Byline: Dincer Yildizdas (1), Hacer Yapicioglu (2), Umit Celik (3), Yasar Sertdemir (4), Emre Alhan (3) Keywords: Terlipressin; Epinephrine; Septic shock; Children Abstract: Objective To evaluate the effect of terlipressin on oxygenation, PaO.sub.2/FIO.sub.2, heart rate, mean arterial pressure, and mortality in children with septic shock refractory to high doses of dopamine/dobutamine and adrenaline. Design and setting A randomized, nonblind study in the pediatric intensive care unit of a university hospital. Patients and measurements We studied 58 children with septic shock and refractory hypotension despite fluid loading and high doses of catecholamines, randomly enrolled to terlipressin (TP, na-=a-30) or control (na-=a-28). TP was administered as intravenous bolus doses of 20a-ug/kg every 6a-h for a maximum of 96a-h. Hemodynamic changes, PaO.sub.2/FIO.sub.2 rates, length of stay, and mortality rate in PICU were recorded prospectively. Results Mean arterial pressure and PaO.sub.2/FIO.sub.2 significantly increased, and heart rate significantly decreased 30a-min after each TP treatment, but mortality did not differ from control (67.3% vs. 71.4%). Mean stay in the PICU was shorter in the TP group (13.4a-+-a-7.9 vs. 20.2a-+-a-9.7a-days and was longer among nonsurvivors of the TP group vs. control (10.4a-+-a-6.9 vs. 6.2a-+-a-3.4a-days). Blood urea nitrogen, creatinine, AST, ALT, and urine output of patients in the TP group did not change after terlipressin. Conclusions Although terlipressin infusion had no effect on mortality, it significantly increases mean arterial pressure, PaO.sub.2/FIO.sub.2, and survival time in nonsurvivors. Terlipressin seems to cause no adverse effect but warrants further evaluation as a rescue therapy in refractory septic shock. Author Affiliation: (1) Faculty of Medicine, Department of Pediatrics, Division of Intensive Care Unit, Cukurova University, 01330, Balcali, Adana, Turkey (2) Faculty of Medicine, Department of Pediatrics, Division of Neonatology, Cukurova University, 01330, Adana, Turkey (3) Faculty of Medicine, Department of Pediatrics, Division of Infectious Disease, Cukurova University, 01330, Adana, Turkey (4) Faculty of Medicine, Department of Biostatistics, Cukurova University, 01330, Adana, Turkey Article History: Registration Date: 27/11/2007 Received Date: 21/11/2006 Accepted Date: 13/11/2007 Online Date: 19/12/2007

Byline: Sanjay Subramanian (1,2), Murat Yilmaz (1,3), Ahmer Rehman (1), Rolf D. Hubmayr (1,4), Bekele Afessa (1), Ognjen Gajic (1) Keywords: Septic shock; Resuscitation; Vasopressor Abstract: Objective The optimal role of vasopressor therapy in septic shock is not known. We hypothesized that the variability in the use of vasopressors to treat hypotension is associated with subsequent organ failures. Design Retrospective observational single-center cohort study. Setting Tertiary care hospital. Patients and participants Consecutive patients with septic shock. Measurement and results Ninety-five patients were enrolled. Serial blood pressure recordings and vasopressor use were collected during the first 12a-h of septic shock. Median duration of hypotension that was not treated with vasopressors was 1.37a-h (interquartile range [IQR] 0.62--2.66). Based on the observed variability, we evaluated liberal (duration of untreated hypotensiona-a-a-a-median) vasopressor therapy. Compared with patients who received conservative vasopressor therapy, patients treated liberally had similar baseline organ impairment [median Sequential Organ Failure Assessment (SOFA) score 8 vs. 8, pa-=a-0.438] were more likely to be younger (median age 70 vs. 77a-years, pa-=a-0.049), to require ventilator support (78 vs. 49%, pa- Conclusions In our retrospective study, early adequate antibiotics and achieving adequate global perfusion, but not liberal vasopressor therapy, were associated with improved organ failures after septic shock. Clinical trials which compare conservative vs. liberal vasopressor therapy are warranted. Author Affiliation: (1) Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Mayo Clinic, 200 First Street SW, 55905, Rochester, MN, USA (2) Department of Critical Care, The Everett Clinic, 98205, Everett, Washington, USA (3) Department of Anesthesiology and Critical Care, Akdeniz University, 07070, Antalya, Turkey (4) Mayo Epidemiology and Translational Research in Intensive Care (M.E.T.R.I.C.), Mayo Clinic, 200 First Street SW, 55905, Rochester, MN, USA Article History: Registration Date: 05/09/2007 Received Date: 05/03/2007 Accepted Date: 11/08/2007 Online Date: 09/10/2007 Article note: Electronic supplementary material The online version of this article (doi: 10.1007/s00134-007-0862-1) contains supplementary material, which is available to authorized users.

Byline: Andrea Morelli (1,5), Monica Rocco (1), Giorgio Conti (2), Alessandra Orecchioni (1), Andrea Gaetano (3), Giuliana Cortese (3), Flaminia Coluzzi (1), Enrico Vernaglione (1), Paolo Pelaia (4), Paolo Pietropaoli (1) Keywords: Gastric mucosal perfusion; Septic shock; Terlipressin; Norepinephrine; Laser-Doppler, tonometry Abstract: Objectives To determine the effects of an intravenous bolus dose of a vasopressin analogue, terlipressin (1 mg), on systemic haemodynamic parameters and gastric mucosal perfusion (GMP) in patients with catecholamine-treated septic shock using a gastric tonometry and laser-Doppler flowmetry technique. Design Prospective open label study. Settings Two multidisciplinary intensive care units. Patients Fifteen patients with norepinephrine-treated septic shock. Interventions Every patient with mean arterial pressure between 50 and 55 mmHg treated with high dose norepinephrine received an intravenous bolus dose of terlipressin as last resort therapy. A laser-Doppler probe and tonometer were introduced into the gastric lumen. Measurements and main results Terlipressin produced a decrease in cardiac output (p Conclusions Our findings showed that, in patients with norepinephrine-treated septic shock, terlipressin increased GMP, urine output and creatinine clearance by an increase in mean arterial pressure. Author Affiliation: (1) Department of Anaesthesiology and Intensive Care, University of Rome 'La Sapienza', Viale del Policlinico 155, 00161, Rome, Italy (2) Department of Anaesthesiology and Intensive Care, Catholic University of Rome, Largo F. Vito 1, 00168, Rome, Italy (3) CNR IASI Biomath Laboratory, Largo A. Gemelli 8, 00168, Rome, Italy (4) Department of Anaesthesiology and Intensive Care, Ospedale Torrette, University of Ancona, Via Conca, 60100, Ancona, Italy (5) Via B. Oriani 2, 00197, Rome, Italy Article History: Registration Date: 06/11/2003 Received Date: 04/06/2003 Accepted Date: 03/11/2003 Online Date: 12/12/2003 Article note: This study was funded by an independent research grant from the Department of Anaesthesiology and Intensive Care of the University of Rome 'La Sapienza'.

Byline: A. Barbot (1), N. Venisse (1), F. Rayeh (1), S. Bouquet (1), B. Debaene (1), O. Mimoz (1) Keywords: Teicoplanin; Pharmacokinetics; Pharmacodynamics; Critically ill patients; Subcutaneous route; Safety Abstract: Objective To compare the pharmacokinetic parameters of sequential intravenous and subcutaneous teicoplanin in the plasma of surgical intensive care unit patients. Design and setting Prospective, randomized, crossover study in the surgical ICU of a university hospital. Patients Twelve patients with a suspected nosocomial infection, a serum albumin level higher than 10 g/l, body mass index less than 28 kg/m.sup.2, and estimated creatinine clearance higher than 70 ml/min. Interventions Teicoplanin was first administered intravenously as a loading dose of 6 mg/kg per 12 h for 48 h and then continued at a daily dose of 6 mg/kg. On the fourth day patients were randomized in two groups according to the order of the pharmacokinetic studies. Measurements and results Serial plasma samples were obtained to measure teicoplanin levels. Compared with a 30-min intravenous infusion the peak concentration of teicoplanin after a 30-min subcutaneous administration occurred later (median 7 h, range 5--18) and was lower (16 Aug/ml, 9--31 vs. 73, 53--106). Despite large and unpredictable interindividual differences no significant differences between subcutaneous and intravenous administration were observed in: trough antibiotic concentrations (10 Aug/ml, 6--24 vs. 9, 5--30), the area under the teicoplanin plasma concentration vs. time curves from 0 to 24 h (AUC.sub.0--24h 309 Aug/ml per minute, 180--640 vs. 369, 171--955), the proportion of the dosing interval during which the plasma teicoplanin concentration exceeded 10 Aug/ml (96%, 0--100% vs. 79%, 13--100%), and the ratio of AUC.sub.0--24h to 10 (77, 45--160 vs. 92, 43--239). Conclusions In critically ill patients without vasopressors a switch to the subcutaneous teicoplanin after an initial intravenous therapy seems to give comparable pharmacodynamic indexes of therapeutic success. Author Affiliation: (1) Departement d'Anesthesie-Reanimation Chirurgicale, Centre Hospitalier et Universitaire, Cite de la Miletrie, 86021, Poitiers Cedex, France Article History: Received Date: 26/12/2002 Accepted Date: 15/05/2003 Online Date: 10/07/2003

Byline: E. Combier (1), S. Levacher (2), P. Letoumelin (3), A. Joseph (4), J.-L. Pourriat (2), G. de Pouvourville (1) Abstract: Objectives: To assess the cost-effectiveness of an early treatment of upper gastro-intestinal haemorrages in cirrhotic patients. Design: Utilization data linked to the results of a double-blind, placebo-controlled trial demonstrating the efficacy of the terlipressin-glycerin trinitrate combination (TER-GTN) in the reduction of mortality at day 42 for haemorragic patients due to rupture of oesophageal varices. Setting: Hopital Jean Verdier, Bondy, Assistance Publique-Hopitaux de Paris, France. Subjects: Eighty-four patients included over 2 years by emergency services and hospitalized in an intensive care unit (ICU) for haemorrage, 41 in the 'treated' group and 43 in the 'placebo' group. Main outcome measures: Mortality at day 42, cost per death avoided. Results: The mortality rate in the placebo group was 46.5 % versus 27.5 % in the treated group. The mean length of stay was 5 days longer in the treatment group. The excess cost per death avoided was 25,849 FF. Of this extra cost 27 % was due to treatment and 24 % was due to increased length of stay. The excess cost per case treated was FF 5,097, 10 % of the total cost per stay for rupture of oesophageal varices (ROV). Conclusions: Our results are of the same magnitude as those published by Mac Cormick et al. in the United Kingdom for similar treatment. The extra cost appears to be moderate, and much lower than monoclonal antibody therapy for sepsis. The impact on the study hospital budget did not exceed 1.7 10.sup.--4. Author Affiliation: (1) Ecole Nationale de la Sante Publique, Groupe IMAGE-ENSP, 14 rue du Val d'Osne, F-94 410 Saint-Maurice, France e-mail: gdepouvo@ensp.fr Tel. + 3 31 (43) 96 64 18 Fax + 331(43)96 65 29, FR (2) Department of Anaesthesia and Intensive Care, CHU Jean Verdier, F-93140 Bondy, France, FR (3) Service d'Aide Medicale Urgente, SAMU 93, F-93000 Bobigny, France, FR (4) Annie Chicoye Economics, 33 rue Fortuny F-75017 Paris, France, FR Article note: Received: 23 June 1998 Accepted: 18 January 1999

The antidiuretic hormone arginine vasopressin (AVP) is a powerful vasoconstrictor that modulates free water transport in the kidney and has an important role in the normal regulation of cardiovascular physiology. The increasing concentrations of plasma AVP within the physiologically relevant range can cause vasoconstriction in patients with advanced heart failure.

Byline: M. Westphal (1), C. Ertmer (1), H. Aken (1), H.-G. Bone (1) Keywords: Oxygen consumption; Oxygen delivery; Sepsis; Vasopressin Author Affiliation: (1) Klinik und Poliklinik fur Anasthesiologie und operative Intensivmedizin, Universitatsklinikum Munster, Albert-Schweitzer-Strasse 33, 48149, Munster, Germany Article History: Registration Date: 26/02/2004 Received Date: 30/12/2003 Accepted Date: 13/02/2004 Online Date: 27/03/2004