High-Dosage Fosfomycin Results in Adequate Plasma and Target-Site Exposure in Morbidly Obese and Nonobese Nonhyperfiltration Patients.

The objectives of this study were the identification in (morbidly) obese and nonobese patients of (i) the most appropriate body size descriptor for fosfomycin dose adjustments and (ii) adequacy of the currently employed dosing regimens. Plasma and target site (interstitial fluid of subcutaneous adipose tissue) concentrations after fosfomycin administration (8 g) to 30 surgery patients (15 obese/15 nonobese) were obtained from a prospective clinical trial. After characterization of plasma and microdialysis-derived target site pharmacokinetics via population analysis, short-term infusions of fosfomycin 3 to 4 times daily were simulated. The adequacy of therapy was assessed by probability of pharmacokinetic/pharmacodynamic target attainment (PTA) analysis based on the unbound drug-related targets of an %fT>MIC (the fraction of time that unbound fosfomycin concentrations exceed the MIC during 24 h) of 70 and an fAUC0-24h/MIC (the area under the concentration-time curve from 0 to 24 h for the unbound fraction of fosfomycin relative to the MIC) of 40.8 to 83.3. Lean body weight, fat mass, and creatinine clearance calculated via adjusted body weight (ABW) (CLCRCG_ABW) of all patients (body mass index [BMI] = 20.1 to 52.0 kg/m2) explained a considerable proportion of between-patient pharmacokinetic variability (up to 31.0% relative reduction). The steady-state unbound target site/plasma concentration ratio was 26.3% lower in (morbidly) obese than nonobese patients. For infections with fosfomycin-susceptible pathogens (MIC ≤ 16 mg/L), intermittent "high-dosage" intravenous (i.v.) fosfomycin (8 g, three times daily) was sufficient to treat patients with a CLCRCG_ABW of <130 mL/min, irrespective of the pharmacokinetic/pharmacodynamic indices considered. For infections by Pseudomonas aeruginosa with a MIC of 32 mg/L, when the index fAUC0-24h/MIC is applied, fosfomycin might represent a promising treatment option in obese and nonobese patients, especially in combination therapy to complement ß-lactams, in which carbapenem-resistant P. aeruginosa is critical. In conclusion, fosfomycin showed excellent target site penetration in obese and nonobese patients. Dosing should be guided by renal function rather than obesity status. (This study has been registered in the EU Clinical Trials Register under EudraCT no. 2012-004383-22.).

[Tourniquet use in the Helicopter Emergency Medical Service : Analysis based on data of the DRF Luftrettung (German Air Rescue) in the period 2015-2020]. / Der Einsatz von Tourniquets im Rahmen der Luftrettung : Analyse anhand der Daten der DRF Luftrettung im Zeitraum 2015­2020.

BACKGROUND: In 2016 the first German recommendation for the preclinical use of tourniquets was published. Currently little is known of the frequency of the use of tourniquets in the prehospital setting in Germany. This study evaluated how often a tourniquet is used in a civilian German Helicopter Emergency Medical Service (HEMS). METHOD: After the approval of the scientific working group of the DRF Luftrettung HEMS, the electronic database (HEMSDER) of the DRF Luftrettung HEMS was analyzed for the period 2015-2020 under the abovementioned question. All patients with a tourniquet application were included in the study and a comparison was made with the total trauma cohort and a subgroup analysis between patients who additionally required airway management and patients without additional airway management in the cohort of tourniquet patients. The analysis was mainly descriptive. Parametric test (t-tests and χ2-tests) were used for group comparison. RESULTS: During the study period 67,321 trauma patients were treated and in 866 (1.3% of all trauma patients) a tourniquet was used. The mean age of these patients was 45.9 years (±19.5 years), 710 (84%) were male, 439 (51%) suffered a monotrauma, 296 (34%) suffered multiple trauma, 339 (38%) required a prehospital airway management and 321 (37%) of these were intubated. Significant differences between patients with tourniquet application and the rest of the trauma cohort were detected in general data (monotrauma, polytrauma and high-speed trauma, massive bleeding), vital signs at the scene of the accident (GCS, HF, SpO2) and necessary interventions, such as pressure bandages and use of hemostyptics, tranexamic acid, analgesia, the frequency of intubation and colloidal volume replacement. Due to limitations of the data set we could not obtain information regarding the limb used for the tourniquet, whether a conversion of the tourniquet was carried out and if the tourniquet was used according to the current German trauma guidelines. CONCLUSION: With a frequency of 1.3% the need for a prehospital tourniquet application is low in civilian trauma patients. Monotrauma with isolated extremity injuries represent about half of the patients treated with tourniquets. The other half is represented by multiple injuries or multiple trauma patients who require significantly more invasive measures, such as airway management and more complex on-scene interventions are needed. The available data do not allow any conclusions to be drawn about the location and the quality of the tourniquet application. Future documentation systems should incorporate data on the use of tourniquets, such as the location of use, indications (tactical use/massive bleeding), bleeding control achieved (yes/no) or second tourniquet necessary, conversion (yes/no) and any obvious complications.

[Specific treatment of acute lung failure]. / Spezifische Therapie des akuten Lungenversagens.

Due to a high heterogeneity and dynamic changes in the course of acute respiratory distress syndrome (ARDS), intensive care physicians are faced with extraordinary challenges. While the current definition, pathophysiology and differential diagnoses were previously addressed in this journal, this article focuses on some specific and individualized treatment options. Ventilation treatment with limitation of tidal volumes and pressure amplitudes has been shown to be advantageous with respect to mortality. Nevertheless, because of the multifactorial etiology of ARDS in the context of individual circumstances, this strategy needs to be adjusted to each patient's needs. In recent years it has become increasingly evident that prone positioning, early spontaneous breathing and early mobilization improve the course of the disease. Therefore, an individualized treatment should consider these issues and take the characteristics of the patient and the specific disease progression into account.

Association between night-time surgery and occurrence of intraoperative adverse events and postoperative pulmonary complications.

BACKGROUND: The aim of this post hoc analysis of a large cohort study was to evaluate the association between night-time surgery and the occurrence of intraoperative adverse events (AEs) and postoperative pulmonary complications (PPCs). METHODS: LAS VEGAS (Local Assessment of Ventilatory Management During General Anesthesia for Surgery) was a prospective international 1-week study that enrolled adult patients undergoing surgical procedures with general anaesthesia and mechanical ventilation in 146 hospitals across 29 countries. Surgeries were defined as occurring during 'daytime' when induction of anaesthesia was between 8:00 AM and 7:59 PM, and as 'night-time' when induction was between 8:00 PM and 7:59 AM. RESULTS: Of 9861 included patients, 555 (5.6%) underwent surgery during night-time. The proportion of patients who developed intraoperative AEs was higher during night-time surgery in unmatched (43.6% vs 34.1%; P<0.001) and propensity-matched analyses (43.7% vs 36.8%; P=0.029). PPCs also occurred more often in patients who underwent night-time surgery (14% vs 10%; P=0.004) in an unmatched cohort analysis, although not in a propensity-matched analysis (13.8% vs 11.8%; P=0.39). In a multivariable regression model, including patient characteristics and types of surgery and anaesthesia, night-time surgery was independently associated with a higher incidence of intraoperative AEs (odds ratio: 1.44; 95% confidence interval: 1.09-1.90; P=0.01), but not with a higher incidence of PPCs (odds ratio: 1.32; 95% confidence interval: 0.89-1.90; P=0.15). CONCLUSIONS: Intraoperative adverse events and postoperative pulmonary complications occurred more often in patients undergoing night-time surgery. Imbalances in patients' clinical characteristics, types of surgery, and intraoperative management at night-time partially explained the higher incidence of postoperative pulmonary complications, but not the higher incidence of adverse events. CLINICAL TRIAL REGISTRATION: NCT01601223.

Effect of Intraoperative High Positive End-Expiratory Pressure (PEEP) With Recruitment Maneuvers vs Low PEEP on Postoperative Pulmonary Complications in Obese Patients: A Randomized Clinical Trial.

Importance: An intraoperative higher level of positive end-expiratory positive pressure (PEEP) with alveolar recruitment maneuvers improves respiratory function in obese patients undergoing surgery, but the effect on clinical outcomes is uncertain. Objective: To determine whether a higher level of PEEP with alveolar recruitment maneuvers decreases postoperative pulmonary complications in obese patients undergoing surgery compared with a lower level of PEEP. Design, Setting, and Participants: Randomized clinical trial of 2013 adults with body mass indices of 35 or greater and substantial risk for postoperative pulmonary complications who were undergoing noncardiac, nonneurological surgery under general anesthesia. The trial was conducted at 77 sites in 23 countries from July 2014-February 2018; final follow-up: May 2018. Interventions: Patients were randomized to the high level of PEEP group (n = 989), consisting of a PEEP level of 12 cm H2O with alveolar recruitment maneuvers (a stepwise increase of tidal volume and eventually PEEP) or to the low level of PEEP group (n = 987), consisting of a PEEP level of 4 cm H2O. All patients received volume-controlled ventilation with a tidal volume of 7 mL/kg of predicted body weight. Main Outcomes and Measures: The primary outcome was a composite of pulmonary complications within the first 5 postoperative days, including respiratory failure, acute respiratory distress syndrome, bronchospasm, new pulmonary infiltrates, pulmonary infection, aspiration pneumonitis, pleural effusion, atelectasis, cardiopulmonary edema, and pneumothorax. Among the 9 prespecified secondary outcomes, 3 were intraoperative complications, including hypoxemia (oxygen desaturation with Spo2 ≤92% for >1 minute). Results: Among 2013 adults who were randomized, 1976 (98.2%) completed the trial (mean age, 48.8 years; 1381 [69.9%] women; 1778 [90.1%] underwent abdominal operations). In the intention-to-treat analysis, the primary outcome occurred in 211 of 989 patients (21.3%) in the high level of PEEP group compared with 233 of 987 patients (23.6%) in the low level of PEEP group (difference, -2.3% [95% CI, -5.9% to 1.4%]; risk ratio, 0.93 [95% CI, 0.83 to 1.04]; P = .23). Among the 9 prespecified secondary outcomes, 6 were not significantly different between the high and low level of PEEP groups, and 3 were significantly different, including fewer patients with hypoxemia (5.0% in the high level of PEEP group vs 13.6% in the low level of PEEP group; difference, -8.6% [95% CI, -11.1% to 6.1%]; P < .001). Conclusions and Relevance: Among obese patients undergoing surgery under general anesthesia, an intraoperative mechanical ventilation strategy with a higher level of PEEP and alveolar recruitment maneuvers, compared with a strategy with a lower level of PEEP, did not reduce postoperative pulmonary complications. Trial Registration: ClinicalTrials.gov Identifier: NCT02148692.

[Platelet function disorder in trauma patients, an underestimated problem? Results of a single center study]. / Thrombozytenfunktionsstörung bei Traumapatienten, ein unterschätztes Problem? Ergebnisse einer monozentrischen Untersuchung.

BACKGROUND: Plasmatic coagulation disorders in trauma patients are common and their management is subject to current guidelines. Less evidence exists for platelet function. Although it is known that several trauma-associated factors have a negative influence on platelet function, routine monitoring has not yet become established. METHODS: A retrospective single center study was carried out at a German level 1 trauma center from 2010 to 2016. In all patients fulfilling the requirements for the German Trauma Society (DGU) Traumaregister® who were admitted directly from the scene of the incident, platelet function was analyzed using the Platelet Function Analyzer (PFA 100®) with adenosine diphosphate (ADP) and epinephrine as activation factors. After exclusion of patients with intake of long-term anticoagulant and antiaggregant medication, possible influencing factors of a reduced platelet function were identified. RESULTS: The results from 310 patients (44.0 ± 14.7 years, 76% male, Injury Severity Score, ISS 28.4 ± 14.2 points) were available. A delayed platelet activation was found in 25.5% using ADP and 31% using epinephrine. Laboratory parameters indicated a greater blood loss. Prolonged closure times were associated with an increased transfusion rate of packed red blood cell concentrates and a higher mortality rate. Logistic regression revealed hemoglobin (Hb) and fibrinogen levels at admission to be independent predictors for a decreased platelet activation in the assay with ADP (p < 0.001, Cohen's f = 0.61) and with epinephrine (p < 0.001, f = 0.42). CONCLUSION: Approximately one quarter to one third of primarily admitted trauma patients without long-term anticoagulation medication showed a delayed platelet activation in the PFA-100 test. By considering all trauma patients an even higher rate can be expected. The Hb and fibrinogen levels at admission can be helpful to estimate platelet disorders. The development of platelet assays to guide the resuscitation of individual patients seems to be absolutely necessary. The contribution of platelet disorders to trauma-induced coagulopathy is not sufficiently understood. Regarding the importance assigned to platelet transfusion or administration of desmopressin, these aspects should be the subject of further research.

Intraoperative ventilation settings and their associations with postoperative pulmonary complications in obese patients.

BACKGROUND: There is limited information concerning the current practice of intraoperative mechanical ventilation in obese patients, and the optimal ventilator settings for these patients are debated. We investigated intraoperative ventilation parameters and their associations with the development of postoperative pulmonary complications (PPCs) in obese patients. METHODS: We performed a secondary analysis of the international multicentre Local ASsessment of VEntilatory management during General Anesthesia for Surgery' (LAS VEGAS) study, restricted to obese patients, with a predefined composite outcome of PPCs as primary end-point. RESULTS: We analysed 2012 obese patients from 135 hospitals across 29 countries in Europe, North America, North Africa, and the Middle East. Tidal volume was 8.8 [25th-75th percentiles: 7.8-9.9] ml kg-1 predicted body weight, PEEP was 4 [1-5] cm H2O, and recruitment manoeuvres were performed in 7.7% of patients. PPCs occurred in 11.7% of patients and were independently associated with age (P<0.001), body mass index ≥40 kg m-2 (P=0.033), obstructive sleep apnoea (P=0.002), duration of anaesthesia (P<0.001), peak airway pressure (P<0.001), use of rescue recruitment manoeuvres (P<0.05) and routine recruitment manoeuvres performed by bag squeezing (P=0.021). PPCs were associated with an increased length of hospital stay (P<0.001). CONCLUSIONS: Obese patients are frequently ventilated with high tidal volume and low PEEP, and seldom receive recruitment manoeuvres. PPCs increase hospital stay, and are associated with preoperative conditions, duration of anaesthesia and intraoperative ventilation settings. Randomised trials are warranted to clarify the role of different ventilatory parameters in obese patients. CLINICAL TRIAL REGISTRATION: NCT01601223.

Individualized positive end-expiratory pressure in obese patients during general anaesthesia: a randomized controlled clinical trial using electrical impedance tomography.

Background: General anaesthesia leads to atelectasis, reduced end-expiratory lung volume (EELV), and diminished arterial oxygenation in obese patients. We hypothesized that a combination of a recruitment manoeuvre (RM) and individualized positive end-expiratory pressure (PEEP) can avoid these effects. Methods: Patients with a BMI ≥35 kg m -2 undergoing elective laparoscopic surgery were randomly allocated to mechanical ventilation with a tidal volume of 8 ml kg -1 predicted body weight and (i) an RM followed by individualized PEEP titrated using electrical impedance tomography (PEEP IND ) or (ii) no RM and PEEP of 5 cm H 2 O (PEEP 5 ). Gas exchange, regional ventilation distribution, and EELV (multiple breath nitrogen washout method) were determined before, during, and after anaesthesia. The primary end point was the ratio of arterial partial pressure of oxygen to inspiratory oxygen fraction ( P aO 2 / F iO 2 ). Results: For PEEP IND ( n =25) and PEEP 5 ( n =25) arms together, P aO 2 / F iO 2 and EELV decreased by 15 kPa [95% confidence interval (CI) 11-20 kPa, P <0.001] and 1.2 litres (95% CI 0.9-1.6 litres, P <0.001), respectively, after intubation. Mean ( sd ) PEEP IND was 18.5 (5.6) cm H 2 O. In the PEEP IND arm, P aO 2 / F iO 2 before extubation was 23 kPa higher (95% CI 16-29 kPa; P <0.001), EELV was 1.8 litres larger (95% CI 1.5-2.2 litres; P <0.001), driving pressure was 6.7 cm H 2 O lower (95% CI 5.4-7.9 cm H 2 O; P <0.001), and regional ventilation was more equally distributed than for PEEP 5 . After extubation, however, these differences between the arms vanished. Conclusions: In obese patients, an RM and higher PEEP IND restored EELV, regional ventilation distribution, and oxygenation during anaesthesia, but these differences did not persist after extubation. Therefore, lung protection strategies should include the postoperative period. Clinical trial registration: German clinical trials register DRKS00004199, www.who.int/ictrp/network/drks2/en/ .

[Preoperative fasting period of fluids in bariatric surgery]. / Präoperative Flüssigkeitskarenz in der bariatrischen Chirurgie.

BACKROUND: Aspiration of stomach content is a severe complication during general anaesthesia. The DGAI (German Society for Anesthesiology and Intensive Care Medicine) guidelines recommend a fasting period for liquids of 2 h, with a maximum of 400 ml. Preoperative fasting can affect the patients' recovery after surgery due to insulin resistance and higher protein catabolism as a response to surgical stress. OBJECTIVES: The aim of the study was to compare a liberal fasting regimen consisting of up to 1000 ml of liquids until 2 h before surgery with the DGAI recommendation. MATERIALS AND METHODS: The prospective observational clinical study was approved by the ethics committee of the University of Leipzig. In the liberal fasting group (Glib) patients undergoing bariatric surgery were asked to drink 1000 ml of tea up to 2 h before surgery. Patients assigned to the restrictive fasting group (Gres) who were undergoing nonbariatric abdominal surgery were asked to drink no more than 400 ml of water up to 2 h preoperatively. Right after anaesthesia induction and intubation a gastric tube was placed, gastric residual volume was measured and the pH level of gastric fluid was determined. Moreover, the occurrence of aspiration was monitored. RESULTS: In all, 98 patients with a body mass index (BMI) of Glib 51.1 kg/m2 and Gres 26.5 kg/m2 were identified. The preoperative fasting period of liquids was significantly different (Glib 170 min vs. Gres 700 min, p < 0.001). There was no difference regarding the residual gastric volume (Glib 11 ml, Gres 5 ml, p = 0.355). The pH of gastric fluid was nearly similar (Glib 4.0; Gres 3.0; p = 0.864). Aspiration did not occur in any patient. CONCLUSIONS: There is evidence suggesting that a liberal fluid fasting regimen (1000 ml of fluid) in the preoperative period is safe in patients undergoing bariatric surgery.

S2e guideline: positioning and early mobilisation in prophylaxis or therapy of pulmonary disorders : Revision 2015: S2e guideline of the German Society of Anaesthesiology and Intensive Care Medicine (DGAI).

The German Society of Anesthesiology and Intensive Care Medicine (DGAI) commissioneda revision of the S2 guidelines on "positioning therapy for prophylaxis or therapy of pulmonary function disorders" from 2008. Because of the increasing clinical and scientificrelevance the guidelines were extended to include the issue of "early mobilization"and the following main topics are therefore included: use of positioning therapy and earlymobilization for prophylaxis and therapy of pulmonary function disorders, undesired effects and complications of positioning therapy and early mobilization as well as practical aspects of the use of positioning therapy and early mobilization. These guidelines are the result of a systematic literature search and the subsequent critical evaluation of the evidence with scientific methods. The methodological approach for the process of development of the guidelines followed the requirements of evidence-based medicine, as defined as the standard by the Association of the Scientific Medical Societies in Germany. Recently published articles after 2005 were examined with respect to positioning therapy and the recently accepted aspect of early mobilization incorporates all literature published up to June 2014.

[Short version S2e guidelines: "Positioning therapy and early mobilization for prophylaxis or therapy of pulmonary function disorders"]. / Kurzversion S2e-Leitlinie - "Lagerungstherapie und Frühmobilisation zur Prophylaxe oder Therapie von pulmonalen Funktionsstörungen".

The German Society of Anesthesiology and Intensive Care Medicine (DGAI) commissioned a revision of the S2 guidelines on "positioning therapy for prophylaxis or therapy of pulmonary function disorders" from 2008. Because of the increasing clinical and scientific relevance the guidelines were extended to include the issue of "early mobilization" and the following main topics are therefore included: use of positioning therapy and early mobilization for prophylaxis and therapy of pulmonary function disorders, undesired effects and complications of positioning therapy and early mobilization as well as practical aspects of the use of positioning therapy and early mobilization. These guidelines are the result of a systematic literature search and the subsequent critical evaluation of the evidence with scientific methods. The methodological approach for the process of development of the guidelines followed the requirements of evidence-based medicine, as defined as the standard by the Association of the Scientific Medical Societies in Germany. Recently published articles after 2005 were examined with respect to positioning therapy and the recently accepted aspect of early mobilization incorporates all literature published up to June 2014.

Pumpless extracorporeal CO(2) removal restores normocapnia and is associated with less regional perfusion in experimental acute lung injury.

BACKGROUND: Lung protective ventilation may lead to hypoventilation with subsequent hypercapnic acidosis (HA). If HA cannot be tolerated or occurs despite increasing respiratory rate or buffering, extracorporeal CO2-removal using a percutaneous extracorporeal lung assist (pECLA) is an option. We hypothesised that compensation of HA using pECLA impairs regional perfusion. To test this hypothesis we determined organ blood flows in a lung-injury model with combined hypercapnic and metabolic acidosis. METHODS: After induction of lung injury using hydrochloric acid (HCl) aspiration and metabolic acidosis by intravenous HCl infusion in nine pigs, an arterial-venous pECLA device was inserted. In randomised order, four treatments were tested: pECLA shunt (1) with and (2) without HA, and clamped pECLA shunt (3) with and (4) without HA. Regional blood flows were measured with the coloured microsphere technique. RESULTS: HA resulted in higher perfusion in adrenal glands, spleen and parts of splanchnic area (P < 0.05) compared with normocapnia. During CO2-removal with pECLA, regional perfusion decreased to levels comparable with those without pECLA and normocapnia. Cardiac output (CO) increased during HA without a pECLA shunt and was highest during HA with a pECLA shunt compared with normocapnia. During CO2-removal with pECLA, this variable decreased but stayed higher than during normocapnia with clamped pECLA shunt (P < 0.05). CONCLUSION: In our lung-injury model, HA was associated with increased systemic and regional blood flow in several organs. pECLA provides effective CO2 removal, requiring a higher CO for perfusion of the pECLA device without improvement of regional organ perfusion.

Repinotan, a selective 5-HT1A-R-agonist, antagonizes morphine-induced ventilatory depression in anesthetized rats.

BACKGROUND: Spontaneous breathing during mechanical ventilation improves arterial oxygenation and cardiovascular function, but is depressed by opioids during critical care. Opioid-induced ventilatory depression was shown to be counteracted in anesthetized rats by serotonin(1A)-receptor (5-HT(1A)-R)-agonist 8-OH-DPAT, which cannot be applied to humans. Repinotan hydrochloride is a selective 5-HT(1A)-R-agonist already investigated in humans, but the effects on ventilation and nociception are unknown. In this study, we sought to establish (a) the effects of repinotan on spontaneous breathing and nociception, and (b) the interaction with the standard opiate morphine. METHODS: The dose-dependent effects of repinotan, given alone or in combination with morphine, on spontaneous minute ventilation (MV) and nociceptive tail-flick reflex latencies (TFLs) were measured simultaneously in spontaneously breathing anesthetized rats. An additional series with NaCl 0.9% and the 5-HT(1A)-R-antagonist WAY 100 135 served as controls. RESULTS: (a) Repinotan dose-dependently activated spontaneous breathing (MV, mean [95% confidence interval]; 53% [29%-77%]) of pretreatment level) and suppressed nociception (TLF, 91% maximum possible effect [68%-114%]) with higher doses of repinotan (2-200 µg/kg). On the contrary, nociception was enhanced with a small dose of repinotan (0.2 µg/kg; TFL, -47% maximum possible effect [-95% to 2%]). Effects were prevented by 5-HT(1A)-antagonist WAY 100 135. (B) Morphine-induced depression of ventilation (MV, -72% [-100% to -44%]) was reversed by repinotan (20 µg/kg), which returned spontaneous ventilation to pretreatment levels (MV, 18% [-40% to 77%]). The morphine-induced complete depression of nociception was sustained throughout repinotan and NaCl 0.9% administration. Despite a mild decrease in mean arterial blood pressure, there were no serious cardiovascular side effects from repinotan. CONCLUSIONS: The 5-HT(1A)-R-agonist repinotan activates spontaneous breathing in anesthetized rats even in morphine-induced ventilatory depression. The potency of 5-HT(1A)-R-agonists to stimulate spontaneous breathing and their antinociceptive effects should be researched further.

Risk of target non-attainment in obese compared to non-obese patients in calculated linezolid therapy.

OBJECTIVES: The aim was to characterize linezolid population pharmacokinetics in plasma and interstitial space fluid of subcutaneous adipose tissue (target site) of obese compared with non-obese patients and to determine dosing regimens enabling adequate therapy using Monte Carlo simulations. METHODS: In this prospective, parallel group, open-label, controlled, single-centre trial, 30 surgery patients (15 obese, 15 non-obese) received 600 mg of intravenous linezolid. A population pharmacokinetic analysis characterizing plasma and microdialysis-derived target site pharmacokinetics was followed by Monte Carlo simulations using twice/thrice daily 600-1200 mg short-term and extended infusions of linezolid. Adequacy of therapy was assessed by the probability of pharmacokinetic/pharmacodynamic target attainment for time and exposure-related indices. RESULTS: In the model, lean body weight and obesity status largely explained between-patient variability in linezolid PK parameters (12.0-44.9%). Both factors caused lower area under the concentration-time curve in typical obese patients in plasma (-20.4%, 95% CI -22.0% to -15.9%) and at target-site (-37.7%, 95% CI -47.1% to -24.2%) compared with non-obese patients. Probability of target attainment showed improvement with increasing linezolid doses. Depending on lean body weight, adequate therapy was partially attained for 900- and 1200-mg linezolid doses and minimum inhibitory concentrations (MICs) ≤2 mg/L (probability of target attainment 62.5-100%) but could not be reached for MIC = 4 mg/L (probability of target attainment ≤82.3%). Additionally, lower linezolid distribution into the target site in obese patients as described above might compromise the plasma-based probability of target attainment analysis. DISCUSSION: This analysis revealed risks of linezolid underdosing in empirical antibiotic therapy of most resistant bacteria for obese and non-obese patients. Doubling the standard dose is associated with adequate probability of target attainment throughout most body masses for MIC ≤2 mg/L. Further clinical studies with adjusted dosing regimens in for example intensive care patients are needed.

Measurement of soft tissue drug concentrations in morbidly obese and non-obese patients - A prospective, parallel group, open-labeled, controlled, phase IV, single center clinical trial.

BACKGROUND: Pharmacokinetic (PK) and pharmacodynamic (PD) data on perioperative antibiotic prophylaxis or antibiotic therapy are rare in patients suffering from morbid obesity. Furthermore, dosing regimens should be based on PK/PD models that ensure effective antibiotic exposure not in plasma, but primarily at the site of infection, mostly in the interstitial fluid (ISF). The aim of this trial is to investigate whether current dosing regimens of various antibiotics lead to effective concentrations in the ISF of morbidly obese patients. METHODS: We designed a prospective, parallel group, open-labeled, controlled single center trial to investigate the plasma and tissue pharmacokinetics of the antibiotics linezolid, meropenem, tigecycline, piperacillin/tazobactam, fosfomcyine, cefazolin, metronidazole and as secondary aim the analgesics metamizole and acetaminophen. Inclusion criteria comprise body mass index ≥35 kg/m2 for obese or between 18.5 and 30 kg/m2 for non-obese patients scheduled for elective abdominal surgery. For PK analysis, blood and microdialysate samples of subcutaneous tissue were collected 0-8 h after study drug administration. The primary endpoint is to investigate a possible dependency of the area-under-the-curve (AUC0-8) in the interstitial fluid on body weight and obesity with population based pharmacokinetic analysis. DISCUSSION: Inadequate dosing regimes of antibiotics may be a relevant factor for morbidity and mortality of patients, as well as for the development of bacterial antibiotic resistance. The measurement of plasma and tissue concentrations will provide information necessary for PK/PD-modelling. These data about antibiotic PK/PDcharacteristics in soft tissue and their dependence on weight should help to develop weight-dependent models for calculation of patient's individual doses of different antibiotics. TRIAL REGISTRATION: EU clinical trials register (EudraCT-No. 2012-004383-22) and German Clinical trials Register (DRKS00004776).

Protective intraoperative ventilation with higher versus lower levels of positive end-expiratory pressure in obese patients (PROBESE): study protocol for a randomized controlled trial.

BACKGROUND: Postoperative pulmonary complications (PPCs) increase the morbidity and mortality of surgery in obese patients. High levels of positive end-expiratory pressure (PEEP) with lung recruitment maneuvers may improve intraoperative respiratory function, but they can also compromise hemodynamics, and the effects on PPCs are uncertain. We hypothesized that intraoperative mechanical ventilation using high PEEP with periodic recruitment maneuvers, as compared with low PEEP without recruitment maneuvers, prevents PPCs in obese patients. METHODS/DESIGN: The PRotective Ventilation with Higher versus Lower PEEP during General Anesthesia for Surgery in OBESE Patients (PROBESE) study is a multicenter, two-arm, international randomized controlled trial. In total, 2013 obese patients with body mass index ≥35 kg/m2 scheduled for at least 2 h of surgery under general anesthesia and at intermediate to high risk for PPCs will be included. Patients are ventilated intraoperatively with a low tidal volume of 7 ml/kg (predicted body weight) and randomly assigned to PEEP of 12 cmH2O with lung recruitment maneuvers (high PEEP) or PEEP of 4 cmH2O without recruitment maneuvers (low PEEP). The occurrence of PPCs will be recorded as collapsed composite of single adverse pulmonary events and represents the primary endpoint. DISCUSSION: To our knowledge, the PROBESE trial is the first multicenter, international randomized controlled trial to compare the effects of two different levels of intraoperative PEEP during protective low tidal volume ventilation on PPCs in obese patients. The results of the PROBESE trial will support anesthesiologists in their decision to choose a certain PEEP level during general anesthesia for surgery in obese patients in an attempt to prevent PPCs. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02148692. Registered on 23 May 2014; last updated 7 June 2016.

Severe accidental hypothermia: rewarming strategy using a veno-venous bypass system and a convective air warmer.

OBJECTIVE: To study a rewarming strategy for patients with severe accidental hypothermia using a simple veno-venous bypass in combination with a convective air warmer. SETTING: Eighteen beds in a university hospital intensive care unit. PATIENTS: Four adults admitted with a core temperature less than 30 degrees C. Hypothermia was caused by alcoholic intoxication in three patients and by drug overdose in one patient. MEASUREMENTS AND MAIN RESULTS: All patients were rewarmed by a venovenous bypass and in three cases a convective air warmer was also used. At a bypass flow rate of 100-300 ml/min the mean increase in core temperature was 1.15 degrees C/h (Range: 1.1-1.2 degrees C/h). One patient died 2 days after rewarming as a consequence of a reactivated pancreatitis. The other three patients survived without neurological sequelae. CONCLUSION: This rewarming technique seems safe and effective and allowed the controlled rewarming of our patients who suffered from severe accidental hypothermia

Proportional assist versus pressure support ventilation: effects on breathing pattern and respiratory work of patients with chronic obstructive pulmonary disease.

OBJECTIVE: To investigate the breathing pattern and the inspiratory work of breathing (WOB(I)) in patients with chronic obstructive pulmonary disease (COPD) assisted with proportional assist ventilation (PAV) and conventional pressure support ventilation (PSV). DESIGN: Prospective controlled study. SETTING: Intensive care unit of a university hospital. PATIENTS: Thirteen COPD patients being weaned from mechanical ventilation. INTERVENTIONS: All patients were breathing PSV and two different levels of PAV. MEASUREMENTS AND MAIN RESULTS: During PAV (EVITA 2 prototype, Dräger, Germany), the resistance of the endotracheal tube (R(et)) was completely compensated while the patients' resistive and elastic loads were compensated for by approximately 80 % and 50 % (PAV(80) and PAV(50)), respectively. PSV was adjusted to match the same mean inspiratory pressure (Pinsp(mean)) as during PAV(80). Airway pressure, esophageal pressure and gas flow were measured over a period of 5 min during each mode. Neuromuscular drive (P(0.1)) was determined by inspiratory occlusions. Mean tidal volume (V(T)) was not significantly different between the modes. However, the coefficient of variation of V(T) was 10 +/- 4.%, 20 +/- 13 % and 15 +/- 8 % during PSV, PAV(80) and PAV(50), respectively. Respiratory rate (RR) and minute ventilation (V(E)) were significantly lower during PAV(80) as compared with both other modes, but the differences did not exceed 10 %. PAV(80) and PSV had comparable effects on WOB(I) and P(0.1), whereas WOB(I) and P(0.1) increased during PAV(50) compared with both other modes. CONCLUSION: Mean values of breathing pattern did not differ by a large amount between the investigated modes. However, the higher variability of V(T) during PAV indicates an increased ability of the patients to control V(T) in response to alterations in respiratory demand. A reduction in assist during PAV(50) resulted in an increase in WOB and indices of patient effort.

Determination of functional residual capacity (FRC) by multibreath nitrogen washout in a lung model and in mechanically ventilated patients. Accuracy depends on continuous dynamic compensation for changes of gas sampling delay time.

OBJECTIVE: Validation of an open-circuit multibreath nitrogen washout technique (MBNW) for measurement of functional residual capacity (FRC). The accuracy of FRC measurement with and without continuous viscosity correction of mass spectrometer delay time (TD) relative to gas flow signal and the influence of baseline FIO2 was investigated. DESIGN: Laboratory study and measurements in mechanically ventilated patients. SETTING: Experimental laboratory and anesthesiological intensive care unit of a university hospital. PATIENTS: 16 postoperative patients with normal pulmonary function (NORM), 8 patients with acute lung injury (ALI) and 6 patients with chronic obstructive pulmonary disease (COPD) were included. INTERVENTIONS: Change of FIO2 from baseline to 1.0. MEASUREMENTS AND MAIN RESULTS: FRC was determined by MBNW using continuous viscosity correction of TD(TDdyn), a constant TD based on the viscosity of a calibration gas mixture (TD0) and a constant TD referring to the mean viscosity between onset and end of MBNW (TDmean). Using TDdyn, the mean deviation between 15 measurements of three different lung model FRCs (FRCmeasured) and absolute volumes (FRCmodel) was 0.2%. For baseline FIO2 ranging from 0.21 to 0.8, the mean deviation between FRCmeasured and FRCmodel was -0.8%. However, depending on baseline FIO2, the calculation of FRC using TDmean and TD0 increased the mean deviation between FRCmeasured and FRCmodel to 2-4% and 8-12%, respectively. In patients (n = 30) the average repeatability coefficient was 6.0%. FRC determinations with TDmean and TD0 were 0.8-13.3% and 4.2-23.9% (median 2.7% and 8.7%) smaller than those calculated with TDdyn. CONCLUSION: A dynamic viscosity correction of TD improves the accuracy of FRC determinations by MBNW considerably, when gas concentrations are measured in a sidestream. If dynamic TD correction cannot be performed, the use of constant TDmean might be suitable. However, in patient measurements this can cause an FRC underestimation of up to 13%.