Midodrine also significantly increased seated SBP , but this effect was not different from ergotamine/caffeine (p = 0.621). There was no significant effect of either medication on orthostatic tolerance; however, ergotamine/caffeine improved presyncopal symptoms (p = 0.034). These findings suggest that combination ergotamine and caffeine elicits a seated pressor response that is similar in magnitude to midodrine, and improves symptoms in autonomic failure. Thus, ergotamine/caffeine could be used as an alternate treatment for autonomic failure, in carefully selected patients without comorbid coronary artery disease.Severely affected patients with autonomic failure require pressor agents to counteract the blood pressure fall and improve presyncopal symptoms upon standing. Previous studies suggest that combination ergotamine and caffeine may be effective in the treatment of autonomic failure, but the efficacy of this drug has not been evaluated in controlled trials. Therefore, we compared the effects of ergotamine/caffeine on seated blood pressure and orthostatic tolerance and symptoms in 12 primary autonomic failure patients without history of coronary artery disease. Patients were randomized to receive a single oral dose of placebo, midodrine (5–10 mg), or ergotamine and caffeine  in a single-blind, crossover study. Blood pressure was measured while patients were seated and after standing for up to 10 min, at baseline and at 1 h post-drug. Ergotamine/caffeine increased seated systolic blood pressure (SBP), the primary outcome, compared with placebo (131 ± 19 and 95 ± 12 mmHg, respectively, at 1 h post-drug;  The use of these drugs can be limited by adverse effects, however, and the FDA recently proposed the withdrawal of midodrine due to lack of post-marketing evidence to support its clinical efficacy  and/or ≥10 mmHg decrease in diastolic blood pressure (DBP) within 3 min of standing  were withheld for at least five half-lives before admission. Both PD+ patients, however, remained on carbidopa/levodopa (sinemet) for the duration of their inpatient stay due to safety concerns. All patients were evaluated with standardized autonomic function tests  Low, . OrthostAutonomic failure patients participated in a crossover study with oral placebo, 5 or 10 mg midodrine (Shire PLC) and combination 1 mg ergotamine and 100 mg caffeine  administered on separate days. The doses of midodrine and ergotamine/caffeine have been previously shown to elicit pressor responses in autonomic failure patients . The difference in the AUCSBP between baseline and post-drug (ΔAUCSBP) was used to test whether orthostatic tolerance differed among treatment groups using a random effects model. Comparisons were made only for patients who could stand after all active medications. Differences in orthostatic symptom scores from baseline to 60 min post-administration were compared within each individual drug using Wilcoxon signed-rank non-parametric tests. Data are presented as mean ± 95% confidence interval (CI) unless otherwise specified. All tests were two-tailed, and a p-value < 0.05 was considered significant. Analyses were performed with SPSS  and STATA .We tested the null hypothesis that there is no difference in seated blood pressure following placebo, midodrine, and ergotamine/caffeine administration in autonomic failure. The primary outcome was defined t-test analysis in PS software (Version 3.0.34) . Ergotamine/caffeine significantly increased seated SBP, the primary outcome, as a linear function of time compared with placebo . Similarly, midodrine increased seated SBP compared with placebo . The magnitude of the seated pressor response to midodrine was similar between patients receiving the 5 mg  and 10 mg  doses. There was no significant difference, however, in the seated pressor response between ergotamine/caffeine and midodrine . In this study, 9 out of 12 (75%) patients exhibited an increase in seated SBP ≥ 20 mmHg with ergotamine/caffeine compared with 5 out of 12 (42%) patients for midodrine, a difference that was not significantly different .The average seated SBP during the 30-min baseline period was similar among placebo, ergotamine/caffeine, and midodrine study days , between midodrine and placebo , or between ergotamine/caffeine and midodrine . The orthostatic symptom composite score, as well as the lightheadedness component of this score (Question 1), were reduced at 60 min following ergotamine/caffeine administration  when compared with baseline. In contrast, there was no significant effect of either midodrine or placebo on orthostatic symptom scores . Two patients subsequently stopped taking ergotamine/caffeine, one due to side effects (feeling tense) and the other because the medication was not readily available. A previous study also reported nausea and tachyphylaxis with chronic administration in autonomic failure , acquisition, analysis or interpretation of data , drafting of the manuscript (Amy C. Arnold and Cyndya A. Shibao), critical revision of the manuscript for intellectual content , obtaining funding , study supervision  and statistical analysis (Leena Choi).Amy C. Arnold was supported by American Heart Association grant 11POST7330010. Claudia E. Ramirez reports no disclosures. Leena Choi reports no disclosures. Luis E. Okamoto reports no disclosures. Alfredo Gamboa is supported by NIH grant K23HL95905. André Diedrich reports no disclosures. Italo Biaggioni is a consultant for Chelsea Therapeutics and Astra Zeneca, is funded by NIH grants P01 HL056693 and U54NS065736, and receives research support from Astra Zeneca and Forest Laboratories. David Robertson is a consultant for Chelsea Therapeutics, and is funded by NIH grants P01HL056693.


Purpose. To determine associations between mediators in tears in the whole spectrum of keratoconus (KC); to explore connections between mediators and Scheimpflug parameters; to examine correlations between Scheimpflug parameters and bronchial asthma. Methods. Tear samples were collected from 69 patients and 19 controls. Concentrations of mediators—IL-6, -10; CXCL8, CCL5; MMP-9, -13; TIMP-1; t-PA, PAI-1—were measured by Cytometric Bead Array. Measured Pentacam parameters include keratometry values , corneal thickness , and elevations and indices (including Belin-Ambrósio deviation (BAD-D)). Results. A number of significant positive associations were observed between pairs of mediator concentrations. Significant positive correlations were found between BAD-D and CXCL8/MMP-9 and K2 and MMP-9. Significant negative associations were explored between Pachy Min and CXCL8/t-PA. Significant associations were found between pairs of mediators  and the severity of KC. Significant positive correlation between asthma and the severity of KC was explored. Conclusion. Cooperation of different mediators in tears all taking part in the complex pathomechanism of keratoconus was revealed. Our research verifies that inflammation plays a crucial role in the pathogenesis of KC. Additionally this study confirms the effect of bronchial asthma on keratoconus. Keratoconus (KC) is usually a bilateral, progressive ectatic corneal disorder, usually appearing in puberty –3. The cα, -β; interferon- (IFN-) γ; matrix metalloproteinase- (MMP-) 1, MMP-3, MMP-7, MMP-9, and MMP-13; Cathepsin B; and Lipocalin-1 have been found in the tears of patients with keratoconus [α; IFN-γ; Chemokine (C-C motif) ligand 5 ; lipophilin C; lipophilin A; lactoferrin; α-fibrinogen; zinc-α2-glycoprotein (ZAG); immunoglobulin A (IgA); immunoglobulin κ-chain (IGKC); polymeric immunoglobuline receptor (PIGR); phospholipase A2; cystatin S; cystatin SN and cystatin SA have also been found in the tear fluid [Classically, KC is considered to be a noninflammatory disease . Howeveratoconus –11. Decrar fluid , 10–14. ar fluid .In addition, an association between KC and bronchial asthma has been identified almost 50 years earlier . SeveralIn the past few decades, slit-imaging technologies provided further improvement in corneal imaging. Nowadays, we can measure not only the front but also the back surface of the cornea with pachymetric mapping and can typify corneal architecture in three dimensions. Furthermore, Ambrósio et al. established numerous indices to improve the screening of the ectasia , 20.α, and different stages of KC. The crucial limitations of these studies [There are only a few preliminary studies examining the association between mediators (mainly cytokines) in the tear fluid and the severity of keratoconus. Lema and Durán analyzed 28 eyes , Jun et  studies , 21, 22 In the present study, our goals were to determine associations between the different types of mediators in tear fluid—IL-6, IL-10, chemokine (C-X-C motif) ligand 8 (CXCL8)/IL-8, CCL5/RANTES, MMP-9, MMP-13, TIMP-1, tissue plasminogen activator (t-PA), and plasminogen activator inhibitor (PAI-1)—in the whole spectrum of keratoconic eyes  and normal eyes. An additional goal was to explore associations between these mediators and the Scheimpflug parameters which characterize the severity of keratoconus. Our aim was also to examine the relationship between the Scheimpflug imaging parameters and bronchial asthma in keratoconus.In this prospective study, patients with keratoconus and normal subjects were recruited from the Outpatient Unit, Department of Ophthalmology, Faculty of Medicine, University of Debrecen, Hungary.K2) was <45 diopters (D); moderate, when K2 was between 45 and 52 D; and severe if K2 was >52 D [Kmax Front) was more than 47 D.We examined patients with keratoconus at all stages  and normal, control patients. We have categorized the participants based on the clinical stage of keratoconus, but group allocation was not a factor in the analysis. An eye was diagnosed as having keratoconus where it had one or a combination of the following clinical signs: central or paracentral stromal thinning of the cornea, conical protrusion, Fleischer's ring, Vogt's striae by slit-lamp examination, and topographic changes . The staas >52 D , 24. At as >52 D , ART Maxas >52 D , and PPIas >52 D ; or wherWe included a randomly selected eye from each participant, although both eyes were examined. Eye selection was based on generating random values using Microsoft Excel set to produce numeric indicators with equal probabilities for either eye. Altogether, 69 patients (mean (SD) age 30.7 (10.3), range 13–68 years) with the following diagnoses—severe KC: 25, moderate KC: 21, mild KC: 5 and subclinical KC: 18—and 19 normal controls (mean (SD) age 31.7 (11.5), range 18–67 years) were enrolled in the study. The 69 eyes of the patients represented the whole spectrum of the abnormal, ectatic, and keratoconic corneas, although no such group allocation was made.The exclusion criteria included the existence of active inflammatory or infective systemic or ocular disease, eye rubbing, and current treatment with systemic or local anti-inflammatory drugs. Those eyes that were affected by previous ocular surgery or trauma, as well as those patients who were pregnant or lactating during the course of the study, were also excluded. Written informed consent from each participant, as well as permission from the University of Debrecen Institutional Ethics Committee, was obtained prior to enrollment. The tenets of the Declaration of Helsinki were followed in all procedures during the study.Both eyes of each participant underwent ophthalmological evaluation, including clinical history , automated kerato-refractometry , uncorrected and corrected distance visual acuity determinations, slit-lamp biomicroscopy (under low illumination to avoid reflex tearing), Rotating Scheimpflug tomography , and nonstimulated tear sample collection with glass capillaries.All eyes were examined with a Pentacam HR (software version 1.16r26 and 1.17r139) without the application of any eye drops. Three sequential scans were taken in each eye by the same trained examiner. In short, the patients were asked to keep both eyes open and fixate on the target, in the center of the blue fixation beam. The examiner with the joystick then focuses and obtains a correct alignment with the corneal apex and a perfect focus, and the instrument automatically takes 25 Scheimpflug images within two seconds. The quality of images was checked under the quality specification (QS) window and only the correct measurements (“QS” reads “OK”) were accepted; if the comments were marked yellow or red, the examination was repeated [K1) and steep (K2) meridian; maximal keratometry of the front surface (Kmax Front); corneal astigmatism (Astig); corneal thickness at the pupil's center (Pachy Pupil), at the apex (Pachy Apex) and at the thinnest point of the cornea (Pachy Min); Index of Surface Variation (ISV); Index of Vertical Asymmetry (IVA); Keratoconus Index (KI); Central Keratoconus Index (CKI); Index of Height Asymmetry (IHA); Index of Height Decentration (IHD); front and back elevation at the thinnest location (F.Ele.Th. and B.Ele.Th.); minimal, maximal, and average pachymetric progression indices ; Ambrósio's Relational Thickness (ART); and Belin-Ambrósio deviation index (BAD-D).The following parameters were exported to Microsoft Excel : Holladay equivalent keratometry values in the flat  or serial dilutions of mixed standard cytokines were added to a 12.5 µL suspension of fluorescent cytokine capture beads in multiwell filter microplates. Added to the wells were 12.5 microliters of biotin-conjugated anti-cytokine antibodies, after which the plates were incubated for two hours on a microplate shaker. The wells were emptied and washed with a vacuum filtration manifold. Phycoerythrin-conjugated streptavidin was added to the plate wells, followed by an additional incubation period of one hour and washed as described before. A 150 µL assay buffer was applied to the wells, after which multiparametric data acquisition was executed using a FACS Array cytometer . The data were analyzed with the FlowCytomix Pro 2.3 software (eBioscience). Additional serial dilutions of the standard were applied to achieve better sensitivity and modified standard curves were thus generated in the analysis. The subsequent detection limits were as follows: IL-6: 1.2 pg/mL; IL-10: 1.9 pg/mL; CXCL8 (IL-8): 0.5 pg/mL; CCL5 (RANTES): 25 pg/mL; MMP-9: 95 pg/mL; MMP-13: 50 pg/mL; TIMP-1: 28 pg/mL; t-PA: 4.8 pg/mL; and PAI-1: 13.5 pg/mL.In tear samples, the concentrations of IL-6, IL-10, CXCL8/IL-8, CCL5/RANTES, MMP-9, MMP-13, TIMP-1, t-PA, and PAI-1 were measured using the Cytometric Bead Array method. Combined FlowCytomix Simplex Kits were used with the suitable FlowCytomix Basic Kit, with minor modifications to the manufacturer's orders  . BrieflyWe categorized the participants for descriptive purposes based on clinical severity . Mediator concentration variables were inspected for the distribution shape and natural log transformed  to improve normality. Similarly, Pentacam parameters were subjected to one of these transformations if that improves distributional symmetry.Pentacam parameters were unified in a composite index referred to as the Standardized Pentacam Score. This was calculated by centering, standardizing, and direction correcting the source variables , running a principal component analysis and deriving the first principal component.Associations between all possible pairs of mediator levels, as well as those between mediators in the tear fluid and Scheimpflug parameters, were evaluated using simple linear regression, including a quadratic term by a curvature in the relationship, if required. Associations between pairs of mediators and the Standardized Pentacam Score were assessed using multiple linear regressions adjusted for age, the presence of asthma, and contact lens usage. Mediator variables were used in linear and quadratic forms, and interactions between those terms were also included in order to accommodate the model to curvatures in the outcome space. Relationships were expressed as the overall significance of the mediator pair effect and also as additive differences in the Standardized Pentacam Score at sample-covered locations, defined by mediator pair concentrations versus an arbitrary reference point.A number of significant positive associations were observed between pairs of mediator concentrations in tear fluid collected from KC patients and subjects with normal eyes, as shown in K2 and MMP-9. Significant negative associations were found between Pachy Min and CXCL8 and Pachy Min and t-PA —or 1.32 standard deviations—higher than those of subjects without the condition.There was a history of asthma in five patients (7.25%) and one of contact lens usage in 15 patients (21.74%). A strong, significant positive association between asthma and the Standardized Pentacam Score was found by linear regression adjusted for age and contact lens usage. Asthmatic patients' scores were, on average, an estimated 5.7 units  in the tear fluid of keratoconic patients covering the whole spectrum of the disease . In accordance with earlier studies, we proved that different mediators—including cytokines, chemokines, enzymes, and inhibitors—in the tear fluid cooperate and take part in a complex immunological network –14, 21. K2.MMPs are zinc-dependent endopeptidases, which participate in degrading and remodeling the extracellular matrix, thereby maintaining its integrity during normal conditions. Nevertheless, under pathological conditions, MMPs can support tissue destruction and other inflammatory reactions. TIMP-1 is the inhibitor of MMPs, which prevents pro-MMP activation and, furthermore, presents antiapoptotic properties , 30, 31.Based on our study and others, the collagenolytic milieu of the human cornea seems to be more complex than expected. Further studies are required to understand the exact mechanisms of collagenases and inhibitors.An active form of t-PA converts plasminogen to plasmin and can also degrade several components of the extracellular matrix, triggering the activation of the MMP pathway. Numerous interactions have been observed between the fibrinolytic and MMP systems taking part in proteolytic activation. Plasminogen activators are partially regulated by PAIs, inhibiting this cascade system and, therefore, influencing KC progression . DiffereApart from the elements of the proteolytic and fibrinolytic systems, we have examined different cytokines, such as the proinflammatory IL-6 and chemokine CXCL8/IL-8 and the anti-inflammatory Th2 cytokine IL-10 ; we founα; MMP-9; TIMP-1; t-PA; and serum Angiopoietin-1 [Bronchial asthma is a chronic airway inflammatory disease. The infiltration of eosinophils, mastocytes, and T lymphocytes and the release of several inflammatory mediators play an important role in asthma's pathogenesis , 37. Difoietin-1 , 38–43. oietin-1 –18. We fThe strengths of our study are the large number of participants (88 subjects) and the consideration of a wide range of tear mediators that could be associated with Pentacam parameters. Our study has limitations, such as the lack of examination of enzyme activities, as well as the fact that we did not examine the progression of keratoconus and the effect of asthma medication. In addition, this study does not exclude the role of other inflammatory molecules in the pathophysiology of KC. It would be interesting to measure more and different types of mediators, but this remains to be determined in subsequent studies. However, several new correlations can be revealed from our results that can be the basis for further study of this topic.Keratoconus has a complex pathomechanism, in which many different cytokines, chemokines, enzymes, and inhibitors are involved. This study reveals the cooperation of the different mediators in tear fluid all taking part in this complex immunological network. As far as we know, this is the first study to reveal associations between tear mediators and BAD-D or Pachy Min. Our study confirms that inflammation is involved in the pathogenesis of keratoconus. As a next step, the precise role of these mediators needs to be defined, as well as examination of the progression of KC and exploration of other mediators' functions. These studies might then serve as a platform for finding targets for local inhibition of pathological corneal thinning, or eventual treatment. In addition, our study confirms the effect of bronchial asthma on keratoconus. Further prospective studies are required to examine the effect of the systemic treatment of asthma on the pathomechanism of keratoconus.


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. The order to revise the S2 guideline ‘positioning in prophylaxis or therapy of pulmonary disorders’, which was established in 2008, was issued by the German Society for Anaesthesiology and Intensive Care Medicine (DGAI). Due to increasing clinical and scientific relevance, the guideline was expanded to include the topic area ‘early mobilisation’.‘Guidelines are systematically developed presentations and recommendations with the purpose of assisting physicians and patients in deciding on appropriate measures for medical care  under specific medical conditions.’ .Guidelines for use in positioning therapy and early mobilisation in prophylaxis or therapy of pulmonary disorders aid in decision-making in specific situations. They are based on the current state of scientific knowledge and on procedures proven in practice.Positioning and early mobilisation are supporting concepts in the treatment and prophylaxis of pulmonary disorders, wherein they are intended to supplement basic medical measures , but not to replace them.There is no single ‘ideal’ position for all pulmonary disorders; rather the positioning plan must be customised individually to the circumstances surrounding a patient and condition.A sharp distinction of the indication ‘prophylaxis’ versus ‘therapy’ is not possible for all eligible pulmonary disorders. As in other therapeutic fields, there is frequently a smooth transition between ‘prophylaxis’, ‘early treatment’ and ‘therapy’.On the basis of the present guideline, the majority of patients with pulmonary disorders should respond well to therapy in conjunction with a whole therapeutic plan.Effective teamwork, the introduction of practical algorithms and proper management of emergency situations are the requirement for the safe implementation of positioning methods and, in particular, for early mobilisation. In doing so, the integration of these concepts into everyday work procedures will lead to a routine course of action and increased experience.The use of positioning and early mobilisation throughout the duration of therapy requires the continual critical review of the indication and customisation to the individual progression of the disease.Objectives and methods of the treatment plan must be presented in a transparent manner for all involved .The guideline is based on the following fundamental assumptions:The guideline refers to the following topics of focus:The use of positioning and early mobilisation in prophylaxis of pulmonary disorders.The use of positioning and early mobilisation in treating pulmonary disorders.Undesired effects and complications of positioning and early mobilisation.Practical aspects when using positioning and early mobilisation.The statements made in the guideline with respect to acute respiratory distress syndrome (ARDS) refer to the ‘Berlin definition’ . This inBegin: within a week after an acute incident or recently occurred or worsened symptomsImaging (X-ray or computed tomography (CT) scan of chest): bilateral infiltrations that cannot be explained alone by effusion, pneumothorax or nodulesCause of the oedema: respiratory distress cannot be explained alone through acute heart failure or volume overload Oxygenation: three degrees of severity are differentiatedmild: partial arterial pressure of oxygen (PaO2)/fractional inspiratory concentration of oxygen (FIO2)= 200–299 mm Hg and positive end-expiratory pressure (PEEP)/continuous positive airway pressure (CPAP) ≥ 5 cm H2Omoderate: PaO2/FIO2 = 100–199 mm Hg and PEEP ≥ 5 cm H2Osevere: PaO2/FIO2 ≤ 100 mm Hg and PEEP ≥ 5 cm H2O.All statements in the existing guideline were revised and the formulations were adapted pursuant to the Berlin definition.This guideline is the result of systematic literary research as well as the subsequent critical evaluation of evidence using scientific methods. The methodical approach of the guideline development process corresponds to the requirements for evidence-based medicine as they were defined by the AWMF as a standard. With respect to positioning, recently published papers were studied starting in 2005; the newly incorporated aspect of early mobilisation comprises all previously published literature up to and including 06/2014.The guideline was prepared in the following steps:Definition of the search terms for all topics of focus and determination of the relevant databases:Pulmonary disorders:  respiratory distress syndrome/ARDS, acute lung injury, severe lung injury, atelectasis, shock lung, acute respiratory failure, postoperative respiratory failure, lung failure, lung insufficiency, respiratory failure, respiratory insufficiency, ventilator-associated/induced lung injury, ventilator-associated/induced pneumonia, prevention/prophylaxis pneumonia.Hospital infections: cross infection, nosocomial infection, hospital infection.Ventilated patients, intensive care patients: critically ill, critical illness, catastrophic illness, critical care, intensive care, intensive care unit (ICU), respiratory care units, artificial respiration, mechanical ventilation.Positioning: prone position, supine position, lateral position, sitting/semi-seated position, horizontal position, semi-recumbent position, positioning, rotation, body position, patient positioning, positioning therapy, kinetic therapy, continuous lateral rotation, backrest elevation, axial/body position change, facedown position, side position, posture.Early mobilisation: early ambulation, accelerated ambulation, occupational therapy, physical therapy, mobility therapy, exercise therapy, early mobilisation, early exercise, early activity, physical therapy modalities.Systematic research of scientific literature (University Library Regensburg), but also previously available guidelines, recommendations and expert opinions.www.cebm.net, as of 2001). Due to the fact that the guideline is a revision and not a new development, this schema was also applied.The evaluation of these publications according to the evidence criteria of the Oxford Centre for Evidence-based Medicine , Marburg assumed the methodological guidance of guideline development.The guideline group comprised the following members:Dr. Melanie Bischoff (DGAI), Uta Brückner (German Association for Physiotherapy), Kris Gebhardt (DGAI), Prof. Dr. Dietrich Henzler (DGAI), Carsten Hermes , Prof. Dr. Klaus Lewandowski (DGAI), Prof. Dr. Martin Max (DGAI), Prof. Dr. Thomas Staudinger , Prof. Dr. Michael Tryba (DGAI), PD Dr. Steffen Weber-Carstens (DGAI) and Prof. Dr. Hermann Wrigge (DGAI).Extensive literary research was conducted by the speaker of the guideline group at the University Library of Regensburg in collaboration with the director of the medical section (Dr. Helge Knüttel) based on preformulated keywords. The search was conducted via the German Institute for Medical Documentation and Information (DIMDI). This includes 40 extra databases in addition to Medline, Embase, Cochrane and SciSearch.All papers published in the databases as of 17 May 2005  were inspected. Only German or English-language publications were taken into account. The literary search primarily related to controlled studies, systematic reviews, meta-analyses, case series, case reports and comments/editorials. The focus was on publications involving adult patients. Articles from the paediatric field were only included if statements were recognised that enabled principle and age-independent statements. Only studies conducted on humans were included. Papers relating to animal experimentation were only evaluated if significant pathophysiological conclusions could be made regarding the functional principle of positioning therapy. Articles from textbooks were not used. Informational material from the medical device industry was only used for technical questions.Initially, the literature of the already existing guideline was revised. Of the 287 publications included in the analysis at the time, only 170 articles were taken into consideration. A total of 117 articles  were precluded after updating the data if newer articles regarding the same subject matter had been published.Within the scope of research (May 2005–May 2014), 7051 publications were initially identified based on the search terms. After viewing the abstracts, excluding duplicates and reviewing relevance, 952 publications were analysed at first. After reading the full texts, an additional 653 studies were precluded due to lacking relevance or inadequate study design  or lack of reference . In the analysis, 299 studies were ultimately included and evaluated based on the aforementioned evidence schema. In the course of subsequently designating 29 relevant publications as well as a guideline , ultimately 329 publications were analysed. Of these, 149 articles were included in the final version of the revision, which results in a total of 319 including the 170 articles adopted from the first version  was the basis for the evidence level and recommendation grading schema. It was modified and adapted for use in Germany  . Thus, the essential findings extracted from literature and assessed according to evidence are initially briefly outlined in the guidelines. The recommendation statement including the evaluation is then made. The grading of the recommendation is thus deducible and comprehensible from the previously presented and evaluated clinically scientific statements. Recommendation classifications may deviate from the evidence level if the guideline group deems this necessary based on ethical or clinical aspects, the evaluation of side effects or clinically practical application, for example in the case of cost/benefit considerations.Furthermore, strong recommendations for therapeutic forms or methods may be expressed, for which the available evidence is not sufficient, but which are indispensable for the clinical process. On the other hand, methods or therapeutic principles, for which a strong recommendation would have to be expressed based on the studies, may receive a low recommendation grade due to their limited clinical importance. The reasons of such a deviating evaluation are mentioned in the text.The prone position implies the positioning of a patient by 180° from the supine position. An incomplete prone position means a position between approximately 135° and < 180°.The primary goal of the prone position in patients with acute lung injury is to improve pulmonary gas exchange. Additional goals are to prevent/reduce the lung damage and secretion mobilisation. This involves a significant therapeutic method in addition to an optimised ventilation strategy , 275  changes of the respiratory mechanics, (b) the reduction of the pleural pressure gradient , 227 andRegarding (a): In ventilated patients with acute lung failure, the prone position leads to a reduction of thoracoabdominal compliance , 282. ReRegarding (b): The prone position leads to a homogenisation of pulmonary gas dispersion in healthy lungs  as well Regarding (c): Ventilation in the prone position leads to a delay and reduction of ventilation-induced lung injury in animal experimentation , 46, 2932 elimination during ventilation in the prone position if the settings of the ventilation device remain unchanged, possibly as an expression of a recruitment [In patients with acute respiratory insufficiency and particularly in the stage of ARDS, ventilation in the prone position leads to an acute increase of arterial oxygenation if the settings of the ventilation device are not changed , 307  despite an increase of oxygenation compared to patients who were not placed in the prone position [2/FIO2 < 88 mm Hg), however, a post-hoc analysis [In two broad studies from multiple centres, daily prone positioning (approximately 8 h for 5–10 days) did not lead to a significantly shorter ventilation period or to a survival advantage in patients with modest to moderate ARDS , however, the studies revealed design flaws or a heterogeneous patient group , 280. Thp < 0.001, Odds Ratio (OR) = 0.44). The occurrence of complications did not differ between the groups, although the control group patients demonstrated a substantially higher occurrence of cardiac arrhythmias (evidence level 1a).In one multicentre study with a prospective randomised design , 237 patIn patients with ARDS (PaO2/FIO2 < 150) and a lung-protective ventilation strategy, the early application of a prolonged prone position leads to a substantial decrease in mortality compared to the supine position (evidence level 1a). It is not clear, whether or not repeated prone positioning is suitable for decreasing the incidence of nosocomial pneumonia (evidence level 4).►1 Patients with ARDS and an impairment of arterial oxygenation (PaO2/FIO2 < 150) should be placed in the prone position .The positive effect of the prone position on the gas exchange may occur immediately (≤ 30 min) or with a delay of up to 24 h after repositioning , 242  compared to a method conducted once , 125 .►3 Prone positioning should be concluded in the case of persistent improvement of oxygenation in the supine position (4 h after supine positioning: PaO2/FIO2 ≥ 150 with a PEEP ≤ 10 cm H2O and FIO2 ≤ 0.6) or if multiple positioning attempts remained unsuccessful .The improvement of oxygenation in the prone position is reinforced through the application of PEEP, particularly in the case of diffuse ARDS , 101 . Moreover, ventilation in the prone position implies physiological protection/reduction of ventilation-associated lung injury [Ventilation in the prone position presents a sensible therapeutic perspective in order to implement a lung-protective strategy by adapting various ventilation settings parameters .►5 An evaluation and adjustment of the ventilation mode in the context of a lung-protective strategy should be conducted after each change of position .p < 0.01) [Prone positioning per se is not a method that promotes hypotension or cardiac instability , 299 (ev < 0.01)  at a sig►6 Prior to the application of prone positioning, the patient should be stabilised haemodynamically and the volume status should be balanced. The use of catecholamines is not a contraindication against the prone position .p = 0.015) [In patients demonstrating no abdominal disease, a minimal, though substantial increase of intra-abdominal pressure without intra-abdominal compartment syndrome occurred as a result of prone positioning during a period of up to 2 h , 135 (ev= 0.015)  ►7 CAVE: In patients with abdominal obesity, kidney and liver function should be monitored closely in the event of prolonged prone positioning (expert consensus).Prone positioning may cause an increase of intracranial pressure and (in the case of unchanged haemodynamics) a reduction of cerebral perfusion pressure in the case of acute traumatic or non-traumatic cerebral lesions , 241  could have positive effects on the damaged cerebrum while in the prone position. Moreover, no study has been conducted regarding whether or not the adapted analgosedation could prevent the intracranial pressure increase in the case of an acute cerebral lesion.Sufficient studies were not conducted previously as to whether or not an adaption of the ventilation settings  and risk  .►9 During the positioning method, intracranial pressure should be continuously monitored . The head should be centred during this method and lateral rotation should be avoided . Expert consensus and S1 guidelineIntracranial Pressure.p < 0.001) and upon turning the head to the side, the pressure of the lower eye increased further. Two additional studies from the operative area confirmed these findings [In one prospective, randomised trial, intraocular pressure (IOP) was measured in patients in the prone position in an operative area prior to, during and after the positioning method, wherein the heads of a patient group were additionally turned to the right side at a 45° angle to the prone position . While ifindings , 122 (ev°), the ‘incomplete’ prone position (135°) is also applied because it is perceived as having fewer side effects for patients and is easier to perform for the nursing staff [In addition to the complete prone position  while in a complete prone position occurred at a significantly higher rate than while in the 135position  .►11 The elevation of the upper body while in the prone position may be sensible for preventing an impact on other organs  .p = 0.002) (evidence level 2b).The following complications were described while in the prone positions , 301 fac° position, ‘incomplete prone position’) compared to the 180° position [According to the results of a prospective, randomised study, a lesser frequency of facial oedema was observed due to the modification of the prone position .►13 An open abdomen, spinal instability, increased intracranial pressure, critical cardiac rhythm disorders and manifest shock are contraindications for the prone position. These contraindications may be deviated from in individual cases after consideration for the benefits and risks and following consultation with the specialist disciplines involved .Each positioning process—depending on the body weight of the patient as well as the invasiveness of the therapy —is conducted by three to five nurses and one physician , 304.A.Preparational measures:Within the scope of prone positioning, the use of a special anti-decubitus mattress system is recommended to prevent/reduce pressure ulcers , particularly in patients with an increased decubitus risk  .Catheters, drainages and artificial airways are secured and, if necessary, extended. Prior to positioning, it is necessary to check whether or not it is a ‘difficult-airway-situation’ in order to take potentially suitable measures to ensure the airways . When performing the rotation, the most essential access points should be secured by the person guiding the head of the patient.2) should be set to 1.0.The inspiratory fractional oxygen concentration  ≤ − 2) is necessary for the rotational manoeuvre to avoid coughing, compaction or regurgitation. Ventilation should be customised accordingly. After the positioning manoeuvre, the analgosedation is reduced.B.ExecutionDuring the rotating manoeuvre, monitoring is necessary by means of continuous arterial blood pressure measurement. Various techniques are described for executing the rotating process. It is recommended to focus on one technique that all involved are familiar with , 195 .After the rotating manoeuvre, special measures are taken to reduce pressure around the head, around the pelvis and the knee. Always ensure careful padding particularly in areas prone to decubitus (recommendation grade A). The head and arms should be additionally repositioned in short intervals while in the prone position (recommendation grade 0).D.Special aspects for executing prone positioning:The application of enteral nutrition while in the prone position was studies in multiple trials , 294. InWhile in the prone position, enteral nutrition is possible with a low flow rate (≤ 30 ml/h), however regular reflux checks are suggested .CLRT involves the continuous rotation of the patient around his longitudinal axis in a motor-driven bed system. Depending on the system, a maximum rotational angle of 62° can be achieved on each side.The goals of CLRT are to prevent pulmonary complications , the reduction of pulmonary inflammation as a result of trauma or infection, as well as improving pulmonary gas exchange in ventilated patients. The increase of oxygenation, the incidence of nosocomial pneumonia, as well as the duration of mechanical ventilation and intensive care stays or hospitalisation are classified as parameters for this. However, none of these parameters are established as an adequate surrogate for survival and the quality of survival. Indications for the use of CLRT comprise both prophylactic (prevention of complications) and therapeutic aspects .Comment: In one recommendation from the Paul Ehrlich Society (PEG) ‘Nosocomial Pneumonia: Prevention, Diagnostics, und Therapy’ [, there is no recommendation for the use of CLRT within the scope of a ‘bundle’ for the prevention of ventilator-associated pneumonia. The current recommendations of the Commission for Hospital Hygiene and Infection Prevention (KRINKO) at the Robert Koch Institute [determined based on ‘lacking consistency’ in the trials and meta-analyses that, ‘Therapy with kinetic beds for the prevention of VAP (“ventilator- associated pneumonia”) cannot be recommended at this time.’ As a restriction to this recommendation, it is necessary to adhere to the fact that at the time of the publication from the KRINKO, the prospective randomised publications from Staudinger et al.  and Simonis et al. [were not yet published.Therapy’ , there institute  determinr et al.  and Simos et al.  were notThe use of CLRT requires a targeted indication and safe handling in order to prevent undesired effects. After initiating this method, the persistence of the indication—as with other therapeutic methods as well—should be reviewed daily.The present studies regarding the effect of CLRT on the incidence of respiratory infections are limited by various criteria for the diagnosis of infections of the upper and lower respiratory tracts as well as the lung parenchyma , 265.p = 0.02) and the treatment time in intensive care  was significantly shorter in patients treated with CLRT; the mortality rate did not differ. The study by Simonis et al. on patients in cardiogenic shock [p = 0.028) (evidence level 1b). There are no comparative studies of CLRT with other positioning methods for preventing VAP.In two more recent prospective randomised trials , 265, a ic shock  demonstr►14 The early use of CLRT can be employed in certain groups of ventilated patients as a supplement to prevention of ventilator-associated pneumonia, however, other methods  should not be impacted by this .The treatment period in intensive care was shorter in three out of eight randomised trials compared to conventionally treated patients (evidence level 1b). The length of hospitalisation was shortened due to CLRT in a prospective randomised trial   , 267. ThThe reduction of extravascular lung water (EVLW) in patients with impaired oxygenation (ARDS)   and lead to a less severe organ function disorder up to the fifth day post-trauma compared to patients treated in the supine position   occurred at a slower rate than in the prone position   (recommendation grade A).In the case of contraindications to the prone position, the use of CLRT may be considered for improving oxygenation .In most studies, CLRT was conducted at beginning of intensive care treatment for at least 72 h. The use of CLRT within 2 days after development of a respiratory insufficiency was linked to a significant reduction of intensive care therapy and hospitalisation compared to a later initiation of the method in two studies , 279 .CLRT should be concluded upon stabilisation of the gas exchange in the supine position without rotation, or if a continuous application showed no success over a period of 48 h to no more than 72 h .►17 For ventilation during CLRT, the principles of a lung-protective ventilation strategy should apply .The following complications were described during CLRT: pressure ulcers, ‘intolerance’ , cinetosis, catheter dislocations, nerve damage , 277. InThere is data from two trials regarding the use of CLRT in patients with acute cerebral lesions , 287. NoIn one retrospective trial, an increased complication rate and duration of ventilation during CLRT was determined in patients with spinal lesions, however the severity of neurological deficits in these patients was greater  than in ►18 The same criteria as with the prone position apply for conducting CLRT in patients with acute cerebral lesions. These patients should be monitored by means of continuous intracranial pressure measurement  and may be situated in a moderately high upper body position (inclined position of the bed system).►19 It is necessary to individually consider between potential damage due to CLRT and the expected benefit in the case of severely injured patients .An instable spine, acute shock syndrome and a body weight > 159 kg (according to the manufacturer) are considered to be contraindications for CLRT.Careful positioning requires special protective measures for pressure-sensitive areas  , 224 , nursing and physician activities should be well coordinated with each other . In the case of an invasive, continuous blood pressure measurement, the pressure sensor must be fastened to the bed system at the level of the heart in the median axis in order prevent false measurements during the rotational process. With a proper routine and preparation, CLRT can also be safely used in combination with extracorporeal membrane oxygenation  , pulmonary complications are intended to be prevented and the pulmonary gas exchange improved. This is the result of frequent repositioning or special lateral positioning in the case of unilateral lung damage. The simplicity of the method is beneficial, which can be conducted at any time with minimal additional effort , 141.Effects on haemodynamics and gas exchange were studied, wherein primarily postoperative patients with healthy lungs were studied , 212.Only minimal changes in ventilation and haemodynamics were detected in spontaneous respiration among individuals with healthy lungs . Blood pIn postoperatively ventilated patients without acute respiratory insufficiency, the overall compliance of the respiratory system in the lateral position is reduced compared to the supine position  (evidenc°–90°) did not improve the pulmonary gas exchange compared to the supine position [In postoperatively ventilated patients with healthy lungs and without acute respiratory insufficiency, without atelectasis and with a high tidal volume, the lateral position .In the case of chronic obstructive pulmonary disease (COPD), noninvasive ventilation in the lateral position is possible. However, it does not cause any additional improvement of the gas exchange compared to the supine position  .►21 Proper positioning and interpretation of invasively measured blood pressure values should be particularly ensured in the lateral position .In spontaneous breathing, the lateral position improves oxygenation if the good lung is down , 95, 284In the case of mechanical ventilation and lateral positioning with the good lung down, oxygenation improves , 244 semi-seated position refers to a position, in which—with bent hip and extended or bent knee joints—the upper body and the head of the patient are elevated by a certain degree as opposed to the flat-lying lower extremities  on the other hand. This likewise includes the so-called ‘reclined seated position’, for which there is no date regarding its effects on haemodynamics and lung function. The see Fig. .Fig. 1MoWhat all modifications of the elevated upper body share in common is that the upper body is positioned above the level of the trunk, wherein the angle is at least 30° .As a goal of the clinical trials, the gravitationally dependent effects of the elevated upper body position were studied. In this regard, the prevention of passive regurgitation (pulmonary aspiration of gastric contents) , 113 andThe aspiration of secretion contaminated with bacteria in the gastrointestinal tract and the pharynx is generally perceived as a risk factor and trigger for the development of nosocomial and ventilator-associated pneumonia (VAP). Consequentially, measures that lead to decrease of gastrointestinal reflux and a reduction of the oropharyngeal secretion volume should accompany a lower incidence of nosocomial pneumonia and VAP , 213 (ev2O). A 45° elevated upper body position in these patients lead to a delay of gastroesophageal reflux and to a decrease, though not a complete prevention, of pulmonary aspiration of pharyngeal secretion compared to a flat supine position [Studies are available that have been conducted on patients with orotracheal intubation, who do not have known risk factors for gastroesophageal reflux. All patients were supplied with a nasogastric tube; some were fed enterally. Stress bleeding prophylaxis was conducted and the endotracheal cuff pressure was monitored  be used as a preferred position with reference to numerous limitations in ventilated patients (evidence level 2a). Despite the weakness of the Delphi recommendation, which is due to the weakness of the analysed studies, the guideline group supports this recommendation as it appears practical for clinical use and reflects the limited evidence.A systematic analysis and evaluation of the three randomised trials regarding the impact of the backrest elevation on VAP incidence by means of the Delphi method  did not ►23 The preferred principle position for intubated patients is the backrest elevation position of 20°–45°, preferably ≥ 30°, considering the limitations .For patients with elevated intracranial pressure, specific recommendations will be announced (see ► 27–29).Even in those with healthy lungs, anaesthesia and mechanical ventilation lead to a change of the regional ventilation with the development of atelectasis, particularly in the dorsal and diaphragm areas of the lungs. This effect is likely more distinctive in patients with increased intra-abdominal pressure  because the mobility of the diaphragm is limited and situated in cranial orientation. Even with ARDS, the impaired lung function leads to ventilation disorders and the formation of atelectasis. We must assume that actions for preventing diaphragm dislocation reduce the formation of atelectasis and thus contribute to an improvement of the gas exchange.°–45°) leads to an increase of oxygenation in 32 % of the patients studied (> 20 % compared to the flat supine position) and to an increase of the lung volume [° position lead to a significant reduction of respiratory effort. Patients found the comfort level in this position to be the highest; no impact on the reduction of the weaning process was observed [In one prospective crossover trial in 40 ARDS patients, the backrest elevation  may contribute to an improvement of oxygenation and the respiratory mechanics in patients with ARDS .►25 Within the scope of thedifficult weaningof mechanical ventilation (without the presence of COPD), the elevated upper body (45°) should be used to reduce respiratory effort and to increase the comfort level of the patient .2), a significant reduction of expiratory flow limitation (= improvement of the gas flow) and a reduction of auto PEEP was revealed while in the sitting position (> 45°) compared to the lying position. These effects were not demonstrable in a control cohort (15 patients with BMI < 30 kg/m2) [In one prospective cohort study on 30 ventilated patients with obesity (BMI > 35 kg/m0 kg/m2)  . The backrest elevation position (> 45°) may contribute to an improvement of the respiratory mechanics in ventilated patients with severe obesity (BMI > 35 kg/m2) . Regarding contraindications for the elevated upper body position—see ►28 und ►31The elevated upper body position has been in treating ICP for a long time. Due to gravitationally dependent shifting, the cerebral blood and fluid volume are reduced and ICP decreases. However, the semi-seated position may also lead to an impact on haemodynamics and thus to a reduction of CPP. In patients with normal and elevated ICP, the elevated upper body position normally leads to a reduction of ICP depending on the angle . An acco►27 The application of an elevated upper body position of 15°–30° is sensible in patients with increased intracranial pressure and may contribute to a reduction of intracerebral pressure ►28 A 45° backrest elevation cannot be recommended without limitation in patients with suspicion of increased intracranial pressure due to the fact that cerebral perfusion pressure can become critically degraded with an increasingly elevated position .►29 With respect to the treatment of patients with elevated intracranial pressure, please refer to the S1 guidelineintracranial pressure:‘If possible, an elevated upper body position should be aimed for. The individually optimised upper body position should be regularly evaluated with ICP and CPP controls in the 0° (not in the case of the risk of aspiration or with ventilation), 15° and 30° position. Venous return flow should not be prevented by bending the head’.the head’.2 consumption. Increased respiratory effort must be made by changing the lung volume particularly in patients with chronic obstructive pulmonary disease (COPD). Regarding the effects of the position, however, differences can be expected between patients with a chronic gas exchange disorder and those with acute exacerbation.Background: The most frequent postoperative complications after thoracic procedures are of a pulmonary nature caused by partial respiratory insufficiency as well as postoperative hypermetabolism with increased OIn patients following a thoracotomy, the semi-seated position resulted in a reduction of energy consumption without impacting haemodynamic function through a decrease of respiratory effort and oxygen consumption in the respiratory muscles  .The semi-seated position may cause a reduction of cardiac output, blood pressure and peripheral oxygen supply due to a decrease of venous return to the heart.In patients with ARDS, the semi-seated position or the anti-Trendelenburg position may cause the recognition of an existing volume deficit , which iIn a prospective randomised crossover study on 200 haemodynamically stable ventilated patients with different underlying disease , the posUnder certain conditions, the backrest elevation (45°) may induce significant hypotension. Controlled ventilation (compared to augmented spontaneous ventilation), continuous analgosedation, an increased need for vasopressors, a high PEEP and a high SAP-II score are considered to be risk factors for this (evidence level 2b).►31 The elevated upper body position of 45° is not recommended in the presence of this/these constellation(s). A maximum backrest elevation of 30° should be conducted in these patients .Multiple studies , 296 desThe elevated upper body position with bending of the hip may affect an increase in intra-abdominal pressure (diverted through the bladder) (evidence level 3).►32 In patients with abdominal disease or severe obesity, the anti-Trendelenburg position without bending of the hip should be preferred for the elevated upper body position .In a prospective crossover study with a variation of the upper body position (0°–75°) the pressure on proximal tissue  was measured in healthy test persons . A signiThe elevated upper body position > 30° with bending of the hip can lead to a critical increase of the pressure on the skin in the sacral area.►33 It is recommended with critically ill intensive care patients to reduce bending of the hip while in the elevated upper body position using the anti-Trendelenburg position .Two positions, namely the supine position and the Trendelenburg position are particularly unsuitable for long-term application in critically ill patients and should only be applied in special situations, for example cardiopulmonary resuscitation, volume deficit shock, insertion of central venous catheters. However, the positioning wish of the patient must also be taken into consideration when positioning.The supine position refers to a position, in which the patient lies flat and horizontally on his back.If someone with a normal weight lies in the flat supine position, an increased venous return flow to the heart will occur. Cardiac output, pulmonary blood flow and arterial blood pressure increase, the functional residual capacity (FRC) decreases, the diaphragm is compromised by the abdomen and limited in its mobility. Anaesthesia, analgosedation or muscle relaxants increase the undesired effects . The redobesity supine death syndrome’ [The flat supine position can be dangerous particularly for obese patients. It can lead to acute heart failure, respiratory arrest and pronounced pulmonary gas exchange disorders , 315. Deyndrome’ .Expiratory flow impediments, the development of an auto PEEP as well as a collapse of small respiratory tracts occurred regularly in mechanically ventilated obese patients in the flat supine position if an external ZEEP (zero endexpiratory pressure) or too low of a PEEP level was selected .If there is a combination of COPD and obesity, a tracheomalacia can only be expected in rare cases (3 %) based on a differential diagnosis, which becomes symptomatic in the flat supine position , 165.►34 The flat supine position should not be applied in critically ill patients due to the numerous unfavourable effects on haemodynamics and pulmonary gas exchange .If the application of the flat supine position is absolutely necessary for special medical or nursing measures, it should be limited to the shortest possible period .The Trendelenburg position is a variation of the flat supine position, in which the head is at the lowest position of the body through the inclined positioning of the bed. It was used regularly starting in 1880 by the surgeon, Friedrich Trendelenburg , during urological and gynaecological procedures and remained widely popular in the following decades , 197.The Trendelenburg position is an extreme strain on the respiratory and cardiovascular system of the critically ill patient. Blood is channelled from the lower parts of the body toward the heart and causes a right heart overload. The abdominal organs and—in the case of the obese—the abdominal fat masses press the diaphragm upward and compromise the lungs. The Trendelenburg position leads to a variety of physiological/pathophysiological changes: an increase in the stroke volume of the heart, the pressure on the central veins and pulmonary arteries, the resistance of the vascular system, the right and left ventricular end systolic volume index, cardiac output and intrathoracic blood volume as well as to reduced cerebral blood flow, to reduced systemic oxygenation and an increase of arterial carbon dioxide partial pressure. The FRC decreases; atelectasis formation occurs .The Trendelenburg position is the most hazardous position for the obese , 264. It►35 The Trendelenburg position should not be applied in critically ill patients due to numerous unfavourable effects on haemodynamics, pulmonary gas exchange and the respiratory system .If the application of the Trendelenburg position is absolutely necessary for special medical or nursing measures, it should be limited to a brief period .►36 The Trendelenburg position should principally be avoided in obese patients .mobilisation describes measures involving the patient, which introduce and/or assist passive or active movement exercises and which aim to promote and/or maintain mobility. In contrast, positioning refers to the change of bodily positions with the goal of influencing gravity-related effects [The term  effects , 176.Early mobilisation refers to the beginning of mobilisation within 72 h after admittance to intensive care.Methods for mobilisation are classified in three areas: passive mobilisation, assisted active mobilisation and active mobilisation , 319. ThPassive mobilisation:Passive motions of all extremities in all physiological directionscycling Passive Passive vertical mobilisation Passive transfer to rehabilitation chairAssisted active mobilisation:Active movement exercises in the supine position with manual supportIndependent mobilisation in bed Balance trainingcyclingAssisted Active mobilisation:Sitting on the edge of the bed, torso controlActive mobilisation to the statusAttempting to stand up, walking exercises while standingWalking with and without walking aidsActive cyclingIsotonic movement exercises with walking aidsImmobilisation refers to the idle position of the bodily parts or the entire body for the purpose of treatment or for rest (bed rest). Undesired effects of immobilisation are a general deconditioning, the development of a weakness, rapid fatigue and atrophy of the muscular respiratory pumps and the skeletal muscles, the development of psycho-cognitive deficits and delirium, the emergence of positioning-related skin and soft tissue damage as well as the reduction of haemodynamic responsiveness [The general goals of mobilisation are to promote and maintain mobility as well as to prevent and/or reduce the effects of immobilisation. siveness , 179.goals of mobilisation consist in improving/maintaining skeletal and respiratory muscle function, increasing haemodynamic responsiveness, improving central and peripheral perfusion and muscle metabolism, increasing cognitive competence and mental wellbeing, reducing incidence and duration of delirium, reducing positioning-related skin ulcers and—compared to patients, who were not mobilised early—improving the subsequent health-related quality of life [The specific  of life , 176.When recording and assessing the effects of early mobilisation on the outcome, various relevant parameters are included. These include bodily function outcomes, peripheral muscle strength and function of the muscular respiratory pump, neurocognitive competence, ventilator-free days, ICU stay, hospitalisation, mortality, quality of life and discharge from the hospital.. [. [The following prospective randomised trials are suitable for an analysis: Morris et al.  discover. , signifi.  describe. , 82, 208.  detected.  observed. [.  recognis►37 In principle, early mobilisation should be conducted in all patients treated in intensive care, for whom no exclusion criteria apply .surgical intensive care unit optimal mobility score, which captured the exclusion of serious organ function disorders and the suitability for mobilisation prior to mobilisation. In one prospective study, this score proved to be better suited—compared to other general scores —to determine suitability for mobilisation (evidence level 3).Patient-related requirements and suitability for mobilisation was reviewed in multiple observational studies , 317. Bo►38 Regarding early mobilisation, the following requirements should be present or established:Customised, score-controlled (e.g. RASS) symptom control of pain, fear, agitation and delirium according to the S3 guideline revision ‘Analgosedation’(German Society of Anesthesia and Intensive Care)Sufficient respiratory reserveSufficient cardiovascular reserveThe following serve as reference points for this: average arterial blood pressure > 65 or < 110 mm Hg, systolic blood pressure < 200 mm Hg, heart rate > 40 or < 130/min, arterial oxygen saturation (pulse oxymetry) ≥ 88 %, no higher-dosage vasopressor therapy.If cardiopulmonary instability develops during ongoing mobilisation, the exercise unit should be discontinued until stabilisation returns or conducted to an adapted extent .Clearly defined exclusion criteria for early mobilisation are not designated in the literature. However, the requirement for mobilisation should be evaluated for certain acute situations in a symptom-adapted manner. The following examples are described in the literature , 318:increased intracranial pressureactive bleedingacute myocardial ischaemiaagitated delirium►39 The decision to conduct limited forms of mobilisation (passive or active with assistance) with the specified relative contraindications should be considered in individual cases in light of the benefits and risks .The preparation for mobilisation and monitoring of the patient during the action is described in various observational studies or randomised trials , 317. Th►40 The preparation of early mobilisation comprises the information of the patient, the provisioning of sufficient staff and the securing/extension of structures of the mechanical respiratory tract, the infusion lines or other drainages. During mobilisation, the heart rate, blood pressure and arterial oxygen saturation should be continuously/closed recorded for the monitoring of the vital parameters .►41 In ventilated patients, the ventilation parameters should be continuously featured  In the prospective randomised studies , 270 dee►42 Treatment should begin no later than 72 h after admittance to intensive care and be conducted twice daily with a duration of at least 20 min for the length of stay in intensive care. A gradual approach should be aimed for starting with passive mobilisation on Table . In this2 < 88 %, heart rate increase > 20 % or heart rate < 40 or > 130/min, newly occurring cardiac dysrhythmias, systolic blood pressure > 180 mm Hg or mean blood pressure < 65 mm Hg or > 110 mm Hg (evidence level 2b). Overall, the occurrence of undesired events provided with an incidence of 1.1–4.4 %.The following complications are described in individual cases within the scope of mobilisation: orthostatic dysregulation, patient fall, disconnection of catheters/airway, cardiac dysrhythmias, respiratory fatigue/dyspnoea and agitation/stress , 269. InIn consideration for patient-related requirements and potential exclusion criteria as well as compliance with preparation measures, early mobilisation presents a safe and uncomplicated method.►43 Cancellation of mobilisation is recommended in the event of the following vital parameter changes: SaO2 < 88 %, heart rate increase > 20 % or heart rate < 40 or > 130/min, new cardiac dysrhythmias, systolic blood pressure > 180 mm Hg or mean blood pressure < 65 mm Hg or > 110 mm Hg .standard of care is recommended [standard of care. In a prospective observation study, the regular integration of a physiotherapist in early mobilisation proved to have a better effect on outcome parameters compared to early mobilisation without physiotherapeutic aid [Early mobilisation represents an interdisciplinary, targeted approach in improving the results of intensive care. The establishment of a concept for this tiered, specific approach in consideration for safety aspects was classified as beneficial in multiple publications , 319. A ommended , which eommended  as well.utic aid , 270 .A few observational studies describe that the application of electrical muscle stimulation in critically ill intensive care patients has a positive effect on the preservation of muscle mass and muscle strength , 308. VeAt the moment, no recommendation for the use of electrical muscle stimulation in intensive care patients can be expressed due to the incomplete data Fig. .Fig. 2Al


The reliability of pulse pressure analysis to estimate cardiac output is known to be affected by arterial load changes. However, the contribution of each aspect of arterial load could be substantially different. In this study, we evaluated the agreement of eight non-commercial algorithms of pulse pressure analysis for estimating cardiac output (PPCO) with esophageal Doppler cardiac output (EDCO) during acute changes of arterial load. In addition, we aimed to determine the optimal arterial load parameter that could detect a clinically significant difference between PPCO and the EDCO.We included mechanically ventilated patients monitored with a prototype esophageal Doppler  and an indwelling arterial catheter who received a fluid challenge or in whom the vasoactive medication was introduced or modified. Initial calibration of PPCO was made with the baseline value of EDCO. We evaluated several aspects of arterial load: total systemic vascular resistance , net arterial compliance (C = EDCO-derived stroke volume/pulse pressure), and effective arterial elastance (Ea = 0.9 * systolic blood pressure/EDCO-derived stroke volume). We compared CO values with Bland-Altman analysis, four-quadrant plot and a modified polar plot .A total of 16,964-paired measurements in 53 patients were performed . Agreement of all PPCO algorithms with EDCO was significantly affected by changes in arterial load, although the impact was more pronounced during changes in vasopressor therapy. When looking at different parameters of arterial load, the predictive abilities of Ea and C were superior to TSVR and MAP changes to detect a PPCO-EDCO discrepancy ≥ 10% in all PPCO algorithms. An absolute Ea change > 8.9 ± 1.7% was associated with a PPCO-EDCO discrepancy ≥ 10% in most algorithms.Changes in arterial load profoundly affected the agreement of PPCO and EDCO, although the contribution of each aspect of arterial load to the PPCO-EDCO discrepancies was significantly different. Changes in Ea and C mainly determined PPCO-EDCO discrepancy. Cardiac output (CO) is an essential component in the hemodynamic assessment of critically ill patients and a central target for goal-directed resuscitation in high-risk surgical patients . During Previous studies have demonstrated that changes in arterial load can affect the reliability of pulse pressure-derived cardiac output (PPCO) measurements -9,11,12;The aim of this study was to describe the performance of PPA during arterial load changes when comparing it with an independent reference technique used as the initial calibration. We assumed that changes in arterial load would affect all PPA algorithms, although the contribution of each aspect of arterial load may be substantially different. For this purpose, we first assessed the reliability of eight non-proprietary PPA algorithms for estimating CO during the introduction or modification in dose of vasoactive medication or during intravenous volume administration. Second, we attempted to identify the optimal arterial load parameter able to predict a clinically significant discrepancy between PPCO and the esophageal Doppler cardiac output (EDCO).This study was performed in the 17-bed multidisciplinary intensive care unit of the Hospital de SAS Jerez from September 2011 to October 2012. The protocol was approved by the institutional research ethics committee of the Hospital del SAS de Jerez de la Frontera. Informed consent was deemed unnecessary because of the observational nature of the study and because the protocol was considered to be part of the standard care.Inclusion criteria included any patient who was already monitored with an esophageal Doppler and indwelling arterial catheter for clinical reasons and for whom the attending physician decided to perform a fluid challenge or titrate the dosage of norepinephrine to maintain a desired level of mean arterial pressure (MAP). Patients with known severe valvular regurgitation, atrial fibrillation, or any contraindication to the use of the esophageal Doppler were excluded.Hemodynamic monitoring was performed by using the CardioQ-Combi™ esophageal Doppler monitor . This prototype combined a standard Doppler monitor with eight PPCO algorithms. The Doppler probe was inserted into the esophagus via the nasal or oral route and advanced until the maximal peak velocity of aortic blood flow signal was achieved. The gain setting was then adjusted to obtain the optimal outline of the aortic velocity waveform.All patients had an arterial catheter for continuous arterial pressure monitoring. After zeroing of the system to atmospheric pressure, the arterial waveform was carefully checked by using a fast flush test in order to ensure optimal harmonics of the arterial pressure measurement system. The absence of overdamping/underdamping of the arterial pressure waveform was a prerequisite for hemodynamic measurements. The arterial pressure signal was transferred from the patient bedside monitor to the esophageal Doppler system by using a serial cable. Eight non-proprietary PPA algorithms built into the CardioQ-Combi™ software and PPCO values were continuously displayed in the monitor along with the arterial load parameters. Initial calibration of PPCO was performed by using the EDCO value before any intervention and after stabilization of heart rate and arterial pressure (less than 5% variation for a 1-minute period). A list of all PPCO algorithms analyzed in this study is shown in Table Considering the pulsatile nature of arterial blood, we evaluated different aspects of arterial load . The steTherapeutic interventions were made only according to the decisions of attending physicians. Clinical care was guided by local protocols and the information obtained via EDCO. Subgroups were defined according to patients receiving fluid administration or introduction/modification in vasoactive dose. Fluid administration consisted of 500-mL infusions of crystalloid for a 25- to 30-minute period. Vasopressor changes consisted of stepwise increases or decreases in norepinephrine in 2- to 4-μg/minute increments every 2 to 3 minutes to maintain a desired MAP level. Supportive therapies and ventilatory settings remained constant and vasopressors (if any) unchanged during fluid administration. All patients were under controlled mechanical ventilation.Normal distribution of data was tested by using the D'Agostino-Pearson test. The results are expressed as mean ± standard deviation (SD) or as median and interquartile range (IQR), as appropriate. Bland-Altman analysis for repeated measurements was used to assess the agreement between EDCO and each PPCO algorithm . Bias waθ ± 1.96 SD) in polar plots, according to the method proposed by Critchley and colleagues  for selecting the exclusion zone size.The ability to track EDCO changes by each PPCO algorithm was tested by using a concordance analysis . Concordlleagues . This meU test or an independent Student t test for independent samples, as appropriate. A P value of less than 0.05 was considered statistically significant. All statistical analyses were two-tailed and performed using MedCalc for Windows version 12.3.0 .The relationship between changes in arterial load parameters and discrepancy between EDCO and each PPCO algorithm [EDCO-PCCO discrepancy (%) = (PPCO − EDCO)/EDCO] was assessed by a regression analysis. A discrepancy of at least 10% between techniques after initial calibration was considered clinically significant. For each PPCO algorithm, a receiver operating characteristic (ROC) curve was also constructed for testing the ability of absolute percentage changes on each arterial load parameter to predict an absolute PPCO-EDCO discrepancy of at least 10%. Areas under the ROC curves were compared by using the method described by DeLong and colleagues . DiffereFifty-three consecutive patients were included. Patient characteristics are summarized in Table Overall, the median EDCO value was 6.3 L/minute (IQR 4.9 to 7.2 L/minute), and absolute percentage change throughout all interventions was 4.9% (IQR 2.1% to 9.8%) with a range of change from −46.9% to 57.7%. During the introduction or modification in vasoactive dose, the absolute percentage change for EDCO was 4.5% (IQR 1.8% to 9.7%) with a range of change from −46.9% to 37.7%. After volume administration, EDCO increased 9.5% (IQR 3.8% to 16.3%).The mean CV for EDCO measurements was 2.4% ± 1.3%. The precision and LSC for EDCO were 4.7% and 6.7%, respectively. According to the combined LSC for both techniques, we selected a 9.5% value for central exclusion zone in the concordance analysis.P <0.01 versus patients receiving fluid administration). There were no significant differences between septic and non-septic patients in bias  and PE . However, LOA was wider in the septic group , except for those based on the assessment of systolic area Table . The conChanges in arterial load parameters throughout different interventions are described in Table The ability of absolute percentage changes of each arterial load parameter to detect an absolute PPCO-EDCO discrepancy of at least 10% is detailed in Table In this study, we observed that PPCO agreement with EDCO was greatly affected by changes in arterial load, although the contribution of each aspect of arterial load to the observed discrepancies was significantly different. Changes in Ea and C mainly determined PPCO-EDCO discrepancies, whereas the impact of TSVR and MAP changes was lower. In practice, changes in traditional indices such as TSVR or MAP fail to identify when EDCO and PPCO diverge. On the other hand, the performance of new indices such as Ea and C is significantly better.To our knowledge, this is the first study to demonstrate that (a) arterial load changes during changes in vasopressor therapy and fluid administration significantly affect the agreement between EDCO and PPCO; (b) during fluid loading, arterial load changes are less pronounced than during changes in vasopressor therapy; (c) during fluid administration, EDCO and PPCO algorithms not based on systolic pressure analysis are interchangeable; (d) during vasopressor therapy, the agreement between EDCO and PPCO is severely affected; (e) precision of PPCO algorithms is more affected in patients with sepsis; and (f) the LSC can implement the power of the polar plot concordance analysis.We believe that from our study we can draw some important information that helps us to understand how EDCO and several PPCO algorithms perform when used at the same time. We have observed that changes in the arterial load  were major determinants in discrepancies between EDCO and PPCO. This is the first study to demonstrate that, during a fluid challenge, EDCO and PPCO perform similarly as long as the arterial load does not change. This finding brings strength to the current practice of using less invasive devices to monitor changes in CO during fluid administration ,27. HoweAfter changes in vasopressors therapy, the agreement between EDCO and PPCO was significantly affected. This finding can generate important research hypotheses regarding the need of external calibrations for less invasive devices. Our study suggests that arterial load changes may provide information about when to recalibrate a device. This could represent an important finding that needs to be verified with protocols aiming at recalibrating when a change in arterial load has been observed.Interestingly, our results suggest that the precision of PPA is more affected in patients with sepsis. This finding is consistent with recently demonstrated central-to-peripheral vascular tone decoupling in experimental endotoxic shock . DecouplIn our study, we arbitrarily used the EDCO as our reference technique and we performed an initial calibration of PPCO based on EDCO values. The poor agreement after significant changes in arterial load could be explained as follows: (a) PPCO is significantly affected by these changes and is not reliable, (b) EDCO is significantly affected by these changes and is not reliable, or (c) PPCO and EDCO are both partially affected by these changes. We believe that the third conclusion represents the most likely explanation, but the lack of an additional external calibration prevents us from speculating any further about which technique would be affected more significantly. We argue that our findings support the recommendation of using an external calibration when significant changes in arterial load are suspected . It woulAnother important finding of this study is that the LSC calculation as suggested by Cecconi and colleagues ,30 can bThere are several limitations to our study which need to be addressed. First, our comparison did not include any commercial PPCO algorithms. Nevertheless, although commercially available algorithms have significant differences, they are based on similar assumptions and thus, in theory, are susceptible to similar shortcomings ,5. SeconChanges in arterial load during changes in vasopressor dosage or fluid administration profoundly affect the agreement between EDCO and PPCO. Arterial load changes are less pronounced during fluid loading and this may explain the better agreement between EDCO and PPCO after a fluid challenge. The impact in EDCO-PPCO discrepancy is not equal for all arterial load parameters, the Ea and the C being the most influential variables in all studied algorithms. As long as the absolute Ea change is less than 7% to 11%, the EDCO and PPCO seem interchangeable. The LSC can be used to identify the best cutoff in a concordance analysis.• The agreement between all PPCO algorithms and EDCO was profoundly affected by arterial load changes induced by changes in vasopressor therapy and fluid administration.• The precision of PPCO algorithms was more affected in patients with sepsis.• The contribution of net arterial compliance and effective arterial elastance to the EDCO-PPCO discrepancies was superior to TSVR and MAP changes in all PPCO algorithms.• An absolute Ea change of more than 7% to 11% was associated with a PPCO-EDCO discrepancy of at least 10%.C: net arterial compliance; CO: cardiac output; CV: coefficient of variation; Ea: effective arterial elastance; EDCO: esophageal Doppler-derived cardiac output; IQR: interquartile range; LOA: limits of agreement; LSC: least significant change; MAP: mean arterial pressure; PE: percentage of error; PPA: pulse pressure analysis; PPCO: pulse pressure-derived cardiac output; RLOA: radial limits of agreement; ROC: receiver operating characteristic; SAP: systolic arterial pressure; SD: standard deviation; SV: stroke volume; TSVR: total systemic vascular resistance.MIMG is a consultant for Edwards Lifesciences  and has received travel expenses from Deltex Medical. AGC has received honoraria from Edwards Lifesciences. AR has received honoraria from and serves on an advisory board for LiDCO  and has received honoraria from Covidien , Edwards Lifesciences, and Cheetah Medical . MC in the last 5 years has received honoraria or travel expenses or both from Edwards Lifesciences, LiDCO, Cheetah Medical, Bmeye , Masimo , and Deltex Medical. MGR and RMG declare that they have no competing interests. Except for the esophageal Doppler monitor, all support was provided solely from institutional or departmental sources or both.MIMG conceived and designed the study, participated in the recruitment of patients, performed the statistical analysis, interpreted the data, and wrote the manuscript. MGR participated in the study design, patient recruitment, and data collection; provided technical support; and contributed to the critical review of the manuscript. AGC participated in the study conception and design, interpreted data, and helped draft the manuscript. AR and RMG made substantial contributions to the analysis and interpretation of data, were involved in drafting the manuscript, and contributed to its critical review. MC contributed in the study design, helped in the statistical analysis, interpreted data, and wrote and reviewed the manuscript. All authors read and approved the final manuscript.Additional Tables, Figures and Appendix. Subgroup analyses, impact of individual arterial load parameters and PPA algorithms description.Click here for file