Post-Mortem Extracorporeal Membrane Oxygenation Perfusion Rat Model: A Feasibility Study.

The development of biomedical soft- or hardware frequently includes testing in animals. However, large efforts have been made to reduce the number of animal experiments, according to the 3Rs principle. Simultaneously, a significant number of surplus animals are euthanized without scientific necessity. The primary aim of this study was to establish a post-mortem rat perfusion model using extracorporeal membrane oxygenation (ECMO) in surplus rat cadavers and generate first post vivo results concerning the oxygenation performance of a recently developed ECMO membrane oxygenator. Four rats were euthanized and connected post-mortem to a venous-arterial ECMO circulation for up to eight hours. Angiographic perfusion proofs, blood gas analyses and blood oxygenation calculations were performed. The mean preparation time for the ECMO system was 791 ± 29 s and sufficient organ perfusion could be maintained for 463 ± 26 min, proofed via angiographic imaging and a mean femoral arterial pressure of 43 ± 17 mmHg. A stable partial oxygen pressure, a 73% rise in arterial oxygen concentration and an exponentially increasing oxygen extraction ratio up to 4.75 times were shown. Considering the 3Rs, the established post-mortal ECMO perfusion rat model using surplus animals represents a promising alternative to models using live animals. Given the preserved organ perfusion, its use could be conceivable for various biomedical device testing.

The effect of warm and humidified gas insufflation in gynecological laparoscopy on maintenance of body temperature: a prospective randomized controlled multi-arm trial.

BACKGROUND: Hypothermia is defined as a decrease in body core temperature to below 36 °C. If intraoperative heat-preserving measures are omitted, a patient's temperature will fall by 1 - 2 °C. Even mild forms of intraoperative hypothermia can lead to a marked increase in morbidity and mortality. Using warm and humidified gas insufflation in laparoscopy may help in the maintenance of intraoperative body temperature. METHODS: In this prospective randomized controlled study, we investigated effects of temperature and humidity of the insufflation gas on intra- and postoperative temperature management. 150 patients undergoing gynecologic laparoscopic surgery were randomly assigned to either insufflation with non-warmed, non-humidified CO2 with forced air warming blanket (AIR), humidified warm gas without forced air warming blanket (HUMI) or humidified warm gas combined with forced air warming blanket (HUMI+). We hypothesized that the use of warmed laparoscopic gas would have benefits in the maintenance of body temperature and reduce the occurrence of hypothermia. RESULTS: The use of warm and humidified gas insufflation alone led to more hypothermia episodes with longer duration and longer recovery times as well as significantly lower core body temperature compared to the other two groups. In the comparison of the AIR group and HUMI + group, HUMI + patients had a significantly higher body temperature at arrival at the PACU (Post Anaesthesia Care Unit), had the least occurrence of hypothermia and suffered from less shivering. CONCLUSION: The use of warm and humidified gas insufflation alone does not sufficiently warm the patients. The optimal temperature management is achieved in the combination of external forced air warming and insufflation of warm and humidified laparoscopy gas.

Randomized Clinical Study of Temporary Transvenous Phrenic Nerve Stimulation in Difficult-to-Wean Patients.

Rationale: Diaphragm dysfunction is frequently observed in critically ill patients with difficult weaning from mechanical ventilation. Objectives: To evaluate the effects of temporary transvenous diaphragm neurostimulation on weaning outcome and maximal inspiratory pressure. Methods: Multicenter, open-label, randomized, controlled study. Patients aged ⩾18 years on invasive mechanical ventilation for ⩾4 days and having failed at least two weaning attempts received temporary transvenous diaphragm neurostimulation using a multielectrode stimulating central venous catheter (bilateral phrenic stimulation) and standard of care (treatment) (n = 57) or standard of care (control) (n = 55). In seven patients, the catheter could not be inserted, and in seven others, pacing therapy could not be delivered; consequently, data were available for 43 patients. The primary outcome was the proportion of patients successfully weaned. Other endpoints were mechanical ventilation duration, 30-day survival, maximal inspiratory pressure, diaphragm-thickening fraction, adverse events, and stimulation-related pain. Measurements and Main Results: The incidences of successful weaning were 82% (treatment) and 74% (control) (absolute difference [95% confidence interval (CI)], 7% [-10 to 25]), P = 0.59. Mechanical ventilation duration (mean ± SD) was 12.7 ± 9.9 days and 14.1 ± 10.8 days, respectively, P = 0.50; maximal inspiratory pressure increased by 16.6 cm H2O and 4.8 cm H2O, respectively (difference [95% CI], 11.8 [5 to 19]), P = 0.001; and right hemidiaphragm thickening fraction during unassisted spontaneous breathing was +17% and -14%, respectively, P = 0.006, without correlation with changes in maximal inspiratory pressure. Serious adverse event frequency was similar in both groups. Median stimulation-related pain in the treatment group was 0 (no pain). Conclusions: Temporary transvenous diaphragm neurostimulation did not increase the proportion of successful weaning from mechanical ventilation. It was associated with a significant increase in maximal inspiratory pressure, suggesting reversal of the course of diaphragm dysfunction. Clinical trial registered with www.clinicaltrials.gov (NCT03096639) and the European Database on Medical Devices (CIV-17-06-020004).

Warm and humidified insufflation gas during gynecologic laparoscopic surgery reduces postoperative pain in predisposed patients-a randomized, controlled multi-arm trial.

BACKGROUND: Postoperative pain remains a common problem in gynecologic laparoscopy, especially in head zone-related regions, triggered by intra-abdominal pressure during capnoperitoneum. Humidified and prewarmed insufflation gas may ameliorate pain and be beneficial. METHODS: This prospective randomized controlled parallel group multi-arm single-center study investigated the effects of temperature and humidity of insufflation gas on postoperative pain during gynecologic laparoscopy with a duration ≥ 60 min. Female participants (18-70 years) were blinded and randomly assigned-computer generated-to either insufflation with dry cold CO2 with forced air warming blanket ("AIR"), humidified warm gas without forced air warming blanket ("HUMI"), or humidified warm gas with forced air warming blanket ("HUMI +"). We hypothesized that using humidified warm gas resulted in lower pain scores and less analgesic consumption. The primary endpoint postoperative pain was assessed for different pain localizations every 12 h during 7 days after surgery. Secondary endpoints were demand for painkillers and epidural anesthetics, length of stay in recovery room, and hospital stay. (Registration: ClinicalTrials.gov NCT02781194-completed). RESULTS: 150 participants were randomized. Compared to group "AIR" (n = 48), there was significantly less pain in group "HUMI +" (n = 48) in the recovery room (- 1.068; 95% CI - 2.08 to - 0.061), as well as significantly less ibuprofen use at day two (- 0.5871 g ± 0.258; p-value = 0.0471). Other variables did not change significantly. Stratification for presence of endometriosis or non-previous abdominal surgery in patient history revealed significantly less pain in both groups "HUMI" (n = 50) and "HUMI +" versus group "AIR." Related side effects were not noted. CONCLUSION: In the overall population, the use of warm, humidified insufflation gas did not yield clinically relevant effects; however, in predisposed patients with endometriosis and who could otherwise expect high pain levels, warm and humidified gas may be beneficial.

Speckle tracking ultrasonography as a new tool to assess diaphragmatic function: a feasibility study.

A reliable method of measuring diaphragmatic function at the bedside is still lacking. Widely used two-dimensional (2D) ultrasonographic measurements, such as diaphragm excursion, diaphragm thickness, and fractional thickening (FT) have failed to show clear correlations with diaphragmatic function. A reason for this is that 2D ultrasonographic measurements, like FT, are merely able to measure the deformation of muscular diaphragmatic tissue in the transverse direction, while longitudinal measurements in the direction of contracting muscle fibres are not possible. Speckle tracking ultrasonography, which is widely used in cardiac imaging, overcomes this disadvantage and allows observations of movement in the direction of the contracting muscle fibres, approximating muscle deformation and the deformation velocity. Several studies have evaluated speckle tracking as a promising method to assess diaphragm contractility in healthy subjects. This technical note demonstrates the feasibility of speckle tracking ultrasonography of the diaphragm in a group of 20 patients after an aortocoronary bypass graft procedure. The results presented herein suggest that speckle tracking ultrasonography is able to depict alterations in diaphragmatic function after surgery better than 2D ultrasonographic measurements.

Is sarcopenia a risk factor for reduced diaphragm function following hepatic resection? A study protocol for a prospective observational study.

INTRODUCTION: Sarcopenia is associated with reduced pulmonary function in healthy adults, as well as with increased risk of pneumonia following abdominal surgery. Consequentially, postoperative pneumonia prolongs hospital admission, and increases in-hospital mortality following a range of surgical interventions. Little is known about the function of the diaphragm in the context of sarcopenia and wasting disorders or how its function is influenced by abdominal surgery. Liver surgery induces reactive pleural effusion in most patients, compromising postoperative pulmonary function. We hypothesise that both major hepatic resection and sarcopenia have a measurable impact on diaphragm function. Furthermore, we hypothesise that sarcopenia is associated with reduced preoperative diaphragm function, and that patients with reduced preoperative diaphragm function show a greater decline and reduced recovery of diaphragm function following major hepatic resection. The primary goal of this study is to evaluate whether sarcopenic patients have a reduced diaphragm function prior to major liver resection compared with non-sarcopenic patients, and to evaluate whether sarcopenic patients show a greater reduction in respiratory muscle function following major liver resection when compared with non-sarcopenic patients. METHODS AND ANALYSIS: Transcostal B-mode, M-mode ultrasound and speckle tracking imaging will be used to assess diaphragm function perioperatively in 33 sarcopenic and 33 non-sarcopenic patients undergoing right-sided hemihepatectomy starting 1 day prior to surgery and up to 30 days after surgery. In addition, rectus abdominis and quadriceps femoris muscles thickness will be measured using ultrasound to measure sarcopenia, and pulmonary function will be measured using a hand-held bedside spirometer. Muscle mass will be determined preoperatively using CT-muscle volumetry of abdominal muscle and adipose tissue at the third lumbar vertebra level (L3). Muscle function will be assessed using handgrip strength and physical condition will be measured with a short physical performance battery . A rectus abdominis muscle biopsy will be taken intraoperatively to measure proteolytic and mitochondrial activity as well as inflammation and redox status. Systemic inflammation and sarcopenia biomarkers will be assessed in serum acquired perioperatively. ETHICS AND DISSEMINATION: This trial is open for recruitment. The protocol was approved by the official Independent Medical Ethical Committee at Uniklinik (Rheinish Westphälische Technische Hochschule (RWTH) Aachen (reference EK309-18) in July 2019. Results will be published via international peer-reviewed journals and the findings of the study will be communicated using a comprehensive dissemination strategy aimed at healthcare professionals and patients. TRIAL REGISTRATION NUMBER: ClinicalTrials. gov (EK309-18); Pre-results.

Effects of elevated positive end-expiratory pressure on diaphragmatic blood flow and vascular resistance during mechanical ventilation.

Although mechanical ventilation (MV) is a life-saving intervention, prolonged MV can lead to deleterious effects on diaphragm function, including vascular incompetence and weaning failure. During MV, positive end-expiratory pressure (PEEP) is used to maintain small airway patency and mitigate alveolar damage. We tested the hypothesis that increased intrathoracic pressure with high levels of PEEP would increase diaphragm vascular resistance and decrease perfusion. Female Sprague-Dawley rats (~6 mo) were randomly divided into two groups receiving low PEEP (1 cmH2O; n = 10) or high PEEP (9 cmH2O; n = 9) during MV. Blood flow, via fluorescent microspheres, was determined during spontaneous breathing (SB), low-PEEP MV, high-PEEP MV, low-PEEP MV + surgical laparotomy (LAP), and high-PEEP MV + pneumothorax (PTX). Compared with SB, both low-PEEP MV and high-PEEP MV increased total diaphragm and medial costal vascular resistance (P ≤ 0.05) and reduced total and medial costal diaphragm blood flow (P ≤ 0.05). Also, during MV medial costal diaphragm vascular resistance was greater and blood flow lower with high-PEEP MV vs. low-PEEP MV (P ≤ 0.05). Diaphragm perfusion with high-PEEP MV+PTX and low-PEEP MV were not different (P > 0.05). The reduced total and medial costal diaphragmatic blood flow with low-PEEP MV appears to be independent of intrathoracic pressure changes and is attributed to increased vascular resistance and diaphragm quiescence. Mechanical compression of the diaphragm vasculature may play a role in the lower diaphragmatic blood flow at higher levels of PEEP. These reductions in blood flow to the quiescent diaphragm during MV could predispose critically ill patients to weaning complications.NEW & NOTEWORTHY This is the first study, to our knowledge, demonstrating that mechanical ventilation, with low and high positive-end expiratory pressure (PEEP), increases vascular resistance and reduces total and regional diaphragm perfusion. The rapid reduction in diaphragm perfusion and increased vascular resistance may initiate a cascade of events that predispose the diaphragm to vascular and thus contractile dysfunction with prolonged mechanical ventilation.

Impaired diaphragm resistance vessel vasodilation with prolonged mechanical ventilation.

Mechanical ventilation (MV) is a life-saving intervention, yet with prolonged MV (i.e., ≥6 h) there are time-dependent reductions in diaphragm blood flow and an impaired hyperemic response of unknown origin. Female Sprague-Dawley rats (4-8 mo, n = 118) were randomized into two groups; spontaneous breathing (SB) and 6-h (prolonged) MV. After MV or SB, vasodilation (flow-induced, endothelium-dependent and -independent agonists) and constriction (myogenic and α-adrenergic) responses were measured in first-order (1A) diaphragm resistance arterioles in vitro, and endothelial nitric oxide synthase (eNOS) mRNA expression was quantified. Following prolonged MV, there was a significant reduction in diaphragm arteriolar flow-induced (SB, 34.7 ± 3.8% vs. MV, 22.6 ± 2.0%; P ≤ 0.05), endothelium-dependent (via acetylcholine; SB, 64.3 ± 2.1% vs. MV, 36.4 ± 2.3%; P ≤ 0.05) and -independent (via sodium nitroprusside; SB, 65.0 ± 3.1% vs. MV, 46.0 ± 4.6%; P ≤ 0.05) vasodilation. Compared with SB, there was reduced eNOS mRNA expression (P ≤ 0.05). Prolonged MV diminished phenylephrine-induced vasoconstriction (SB, 37.3 ± 6.7% vs. MV, 19.0 ± 1.9%; P ≤ 0.05) but did not alter myogenic or passive pressure responses. The severe reductions in diaphragmatic blood flow at rest and during contractions, with prolonged MV, are associated with diaphragm vascular dysfunction which occurs through both endothelium-dependent and endothelium-independent mechanisms.NEW & NOTEWORTHY Following prolonged mechanical ventilation, vascular alterations occur through both endothelium-dependent and -independent pathways. This is the first study, to our knowledge, demonstrating that diaphragm arteriolar dysfunction occurs consequent to prolonged mechanical ventilation and likely contributes to the severe reductions in diaphragmatic blood flow and weaning difficulties.

Effect of Long-Term Polytrauma on Ventilator-Induced Diaphragmatic Dysfunction in a Piglet Model.

INTRODUCTION: Mechanical ventilation is known to activate oxidative stress and proteolytic pathways in the diaphragm. Trauma by inducing inflammation and activating proteolytic pathways may potentiate the effects of mechanical ventilation on the diaphragm. In a blunt chest trauma with concomitant injuries we tested the hypothesis that trauma via inflammation further activates the proteolytic pathways and worsens atrophy in the diaphragm. MATERIAL AND METHODS: Piglets were separated into two groups and underwent 72 h of mechanical ventilation. One group received a polytrauma (PT) by unilateral femur fracture, blunt chest trauma with lung contusion, laparotomy with standardized liver incision, and a predefined hemorrhagic shock. The second mechanically ventilated group (MV) did not receive any trauma. A non-ventilated group (Con) served as control.Diaphragmatic fiber dimensions, Western Blot analyses of proteolytic pathways, and lipid peroxidation and messenger ribonucleic acid (mRNA) levels of cytokines and nuclear factor kappa b subunit p65 were measured. RESULTS: Active Caspase-3 was significantly increased in MV (P = 0.019), and in PT (P = 0.02) compared with Con. Nuclear factor kappa b subunit p65, was upregulated in PT (P = 0.010) compared with Con. IL-6 mRNA increased significantly in PT compared with Con (P = 0.0024) but did not differ between Con and MV. CONCLUSION: Trauma and mechanical ventilation induced proteolysis and atrophy in the diaphragm, but only polytrauma induced an inflammatory response in the diaphragm. The additional traumatic inflammatory stimulus did not increase the levels of the prementioned variables. These data underline that inflammation is not a major contributor to ventilator-induced diaphragmatic dysfunction. TRIAL REGISTRY NUMBER: AZ 84-02.04.2014.A265 (Landesamt für Natur-, Umwelt- und Verbraucherschutz, LANUV NRW, Germany).

Heating capabilities of small fluid warming systems.

BACKGROUND: Perioperative temperature management is fundamental to ensure normothermia in patients. Fluid warmers, which have become smaller in size over the past few years, can help to maintain a stable body temperature. Potentially, the reduction of the size may influence the heating performance. METHODS: Therefore, we tested the effectiveness of enFlow®, Fluido compact® and Thermosens® fluid warmers by measuring the inlet and outlet temperature for room-tempered and ice-cooled saline at flow rates of 25, 50, 75 and 100 ml/min. RESULTS: At all examined flow rates, the tested heating devices warmed up room-tempered saline effectively. The enFlow® provided the significantly (p < 0.05) highest outlet temperature throughout all tested flow rates in comparison to the other devices. When ice-cooled saline was used, the enFlow® maintained a stable outlet temperature > 38 °C at all tested flow rates. The Fluido compact® ensured this only at flow rates of 25 and 50 ml/min, while the Thermosens® provided these conditions at flow rates of 25, 50 and 75 ml/min. CONCLUSIONS: The heating capability for room-tempered saline was effective in all tested devices, but with ice-cooled saline enFlow® is superior at high flow rates. At low flow rates the heating capabilities of enFlow®, Fluido compact® and Thermosens® are comparable.

Dexmedetomidine Impairs Diaphragm Function and Increases Oxidative Stress but Does Not Aggravate Diaphragmatic Atrophy in Mechanically Ventilated Rats.

BACKGROUND: Anesthetics in ventilated patients are critical as any cofactor hampering diaphragmatic function may have a negative impact on the weaning progress and therefore on patients' mortality. Dexmedetomidine may display antioxidant and antiproteolytic properties, but it also reduced glucose uptake by the muscle, which may impair diaphragm force production. This study tested the hypothesis that dexmedetomidine could inhibit ventilator-induced diaphragmatic dysfunction. METHODS: Twenty-four rats were separated into three groups (n = 8/group). Two groups were mechanically ventilated during either dexmedetomidine or pentobarbital exposure for 24 h, referred to as interventional groups. A third group of directly euthanized rats served as control. Force generation, fiber dimensions, proteolysis markers, protein oxidation and lipid peroxidation, calcium homeostasis markers, and glucose transporter-4 (Glut-4) translocation were measured in the diaphragm. RESULTS: Diaphragm force, corrected for cross-sectional area, was significantly decreased in both interventional groups compared to controls and was significantly lower with dexmedetomidine compared to pentobarbital (e.g., 100 Hz: -18%, P < 0.0001). In contrast to pentobarbital, dexmedetomidine did not lead to diaphragmatic atrophy, but it induced more protein oxidation (200% vs. 73% in pentobarbital, P = 0.0015), induced less upregulation of muscle atrophy F-box (149% vs. 374% in pentobarbital, P < 0.001) and impaired Glut-4 translocation (-73%, P < 0.0005). It activated autophagy, the calcium-dependent proteases, and caused lipid peroxidation similarly to pentobarbital. CONCLUSIONS: Twenty-four hours of mechanical ventilation during dexmedetomidine sedation led to a worsening of ventilation-induced diaphragm dysfunction, possibly through impaired Glut-4 translocation. Although dexmedetomidine prevented diaphragmatic fiber atrophy, it did not inhibit oxidative stress and activation of the proteolytic pathways.

Acceleration sensors in abdominal wall position as a non-invasive approach to detect early breathing alterations induced by intolerance of increased airway resistance.

BACKGROUND: Early detection of respiratory overload is crucial to mechanically ventilated patients, especially during phases of spontaneous breathing. Although a diversity of methods and indices has been established, there is no highly specific approach to predict respiratory failure. This study aimed to evaluate acceleration sensors in abdominal and thoracic wall positions to detect alterations in breathing excursions in a setting of gradual increasing airway resistance. METHODS: Twenty-nine healthy volunteers were committed to a standardized protocol of a two-minutes step-down spontaneous breathing on a 5 mm, 4 mm and then 3 mm orally placed endotracheal tube. Accelerator sensors in thoracic and abdominal wall position monitored breathing excursions. 15 participants passed the breathing protocol ("completed" group), 14 individuals cancelled the protocol due to subjective intolerance to the increasing airway resistance ("abandoned" group). RESULTS: Gradual increased respiratory workload led to a significant decrease of acceleration in abdominal wall position in the "abandoned" group compared to the "completed" group (p < 0.001), while these gradual accelerating changes were not observed in thoracic wall position (p = 0.484). Thoracic acceleration sensors did not detect any time- and group-specific changes (p = 0.746). CONCLUSIONS: The abdominal wall position of the acceleration sensors may be a non-invasive, economical and practical approach to detect early breathing alterations prior to respiratory failure. TRIAL REGISTRATION: EK 309-15; by the Ethics Committee of the Faculty of Medicine, RWTH Aachen, Aachen, Germany. Retrospectively registered 28th of December 2015.

Functional assessment of the diaphragm by speckle tracking ultrasound during inspiratory loading.

Assessment of diaphragmatic effort is challenging, especially in critically ill patients in the phase of weaning. Fractional thickening during inspiration assessed by ultrasound has been used to estimate diaphragm effort. It is unknown whether more sophisticated ultrasound techniques such as speckle tracking are superior in the quantification of inspiratory effort. This study evaluates the validity of speckle tracking ultrasound to quantify diaphragm contractility. Thirteen healthy volunteers underwent a randomized stepwise threshold loading protocol of 0-50% of the maximal inspiratory pressure. Electric activity of the diaphragm and transdiaphragmatic pressures were recorded. Speckle tracking ultrasound was used to assess strain and strain rate as measures of diaphragm tissue deformation and deformation velocity, respectively. Fractional thickening was assessed by measurement of diaphragm thickness at end-inspiration and end-expiration. Strain and strain rate increased with progressive loading of the diaphragm. Both strain and strain rate were highly correlated to transdiaphragmatic pressure (strain r2 = 0.72; strain rate r2 = 0.80) and diaphragm electric activity (strain r2 = 0.60; strain rate r2 = 0.66). We conclude that speckle tracking ultrasound is superior to conventional ultrasound techniques to estimate diaphragm contractility under inspiratory threshold loading.NEW & NOTEWORTHY Transdiaphragmatic pressure using esophageal and gastric balloons is the gold standard to assess diaphragm effort. However, this technique is invasive and requires expertise, and the interpretation may be complex. We report that speckle tracking ultrasound can be used to detect stepwise increases in diaphragmatic effort. Strain and strain rate were highly correlated with transdiaphragmatic pressure, and therefore, diaphragm electric activity and speckle tracking might serve as reliable tools to quantify diaphragm effort in the future.

Plasma adrenomedullin in critically ill patients with sepsis after major surgery: A pilot study.

PURPOSE: Adrenomedullin is released by different tissues in hypoxia, oxidative stress, and inflammation and is found in general and medical patients and, recently, in sepsis patients in emergency departments. The aim of this study was to evaluate biologically active adrenomedullin that mirrors directly the active peptide levels in plasma of surgical intensive care unit (ICU) patients with sepsis. MATERIALS AND METHODS: In this single-center observational pilot trial, 42 ICU patients with sepsis and 14 patients after major surgery were included after sepsis diagnosis or ICU admission. RESULTS: Patients (66% male) were 70 (median) (interquartile range [IQR], 61-77]) years old and had a body mass index of 26.2 (24.2-29.4) kg/m2. The ICU and hospital length of stay was 8 (1-22) and 17 (8-21) days, respectively. Eight patients had sepsis, 19 developed severe sepsis, and 15 suffered from septic shock. Adrenomedullin increased with severity (sepsis: 25.8 pg/mL [IQR 20.3-40.2], severe sepsis: 84.2 pg/mL [IQR 42.7-118.5], septic shock: 119.7 pg/mL [IQR 83.8-172.6]; P<.0001). Higher adrenomedullin was associated with poor 90-day outcomes (P=.019) and more frequent vasopressor use (P=.001). CONCLUSIONS: This is the first study investigating adrenomedullin in patients with sepsis following major surgery. Higher adrenomedullin on admission is associated with increased vasopressor need and mortality after 90 days. Thus, adrenomedullin may be a useful additional parameter in surgical patients with sepsis.

Kinetics of ventilation-induced changes in diaphragmatic metabolism by bilateral phrenic pacing in a piglet model.

Perioperative necessity of deep sedation is inevitably associated with diaphragmatic inactivation. This study investigated 1) the feasibility of a new phrenic nerve stimulation method allowing early diaphragmatic activation even in deep sedation and, 2) metabolic changes within the diaphragm during mechanical ventilation compared to artificial activity. 12 piglets were separated into 2 groups. One group was mechanically ventilated for 12 hrs (CMV) and in the second group both phrenic nerves were stimulated via pacer wires inserted near the phrenic nerves to mimic spontaneous breathing (STIM). Lactate, pyruvate and glucose levels were measured continuously using microdialysis. Oxygen delivery and blood gases were measured during both conditions. Diaphragmatic stimulation generated sufficient tidal volumes in all STIM animals. Diaphragm lactate release increased in CMV transiently whereas in STIM lactate dropped during this same time point (2.6 vs. 0.9 mmol L-1 after 5:20 hrs; p < 0.001). CMV increased diaphragmatic pyruvate (40 vs. 146 µmol L-1 after 5:20 hrs between CMV and STIM; p < 0.0001), but not the lactate/pyruvate ratio. Diaphragmatic stimulation via regular electrodes is feasible to generate sufficient ventilation, even in deep sedation. Mechanical ventilation alters the metabolic state of the diaphragm, which might be one pathophysiologic origin of ventilator-induced diaphragmatic dysfunction. Occurrence of hypoxia was unlikely.

Influence of weaning methods on the diaphragm after mechanical ventilation in a rat model.

BACKGROUND: Mechanical ventilation (MV) is associated with diaphragm weakness, a phenomenon termed ventilator-induced diaphragmatic dysfunction. Weaning should balance diaphragmatic loading as well as prevention of overload after MV. The weaning methods pressure support ventilation (PSV) and spontaneous breathing trials (SBT) lead to gradual or intermittent reloading of a weak diaphragm, respectively. This study investigated which weaning method allows more efficient restoration of diaphragm homeostasis. METHODS: Rats (n = 8 per group) received 12 h of MV followed by either 12 h of pressure support ventilation (PSV) or intermittent spontaneous breathing trials (SBT) and were compared to rats euthanized after 12 h MV (CMV) and to acutely euthanized rats (CON). Force generation, activity of calpain-1 and caspase-3, oxidative stress, and markers of protein synthesis (phosphorylated AKT to total AKT) were measured in the diaphragm. RESULTS: Reduction of diaphragmatic force caused by CMV compared to CON was worsened with PSV and SBT (both p < 0.05 vs. CON and CMV). Both PSV and SBT reversed oxidative stress and calpain-1 activation caused by CMV. Reduced pAKT/AKT was observed after CMV and both weaning procedures. CONCLUSIONS: MV resulted in a loss of diaphragmatic contractility, which was aggravated in SBT and PSV despite reversal of oxidative stress and proteolysis.

Xenon triggers pro-inflammatory effects and suppresses the anti-inflammatory response compared to sevoflurane in patients undergoing cardiac surgery.

INTRODUCTION: Cardiac surgery encompasses various stimuli that trigger pro-inflammatory mediators, reactive oxygen species and mobilization of leucocytes. The aim of this study was to evaluate the effect of xenon on the inflammatory response during cardiac surgery. METHODS: This randomized trial enrolled 30 patients who underwent elective on-pump coronary-artery bypass grafting in balanced anaesthesia of either xenon or sevoflurane. For this secondary analysis, blood samples were drawn prior to the operation, intra-operatively and on the first post-operative day to measure the pro- and anti-inflammatory cytokines interleukin-6 (IL-6), interleukin-8/C-X-C motif ligand 8 (IL-8/CXCL8), and interleukin-10 (IL-10). Chemokines such as C-X-C motif ligand 12/ stromal cell-derived factor-1α (CXCL12/SDF-1α) and macrophage migration inhibitory factor (MIF) were measured to characterize xenon's perioperative inflammatory profile and its impact on migration of peripheral blood mononuclear cells (PBMC). RESULTS: Xenon enhanced the postoperative increase of IL-6 compared to sevoflurane (Xenon: 90.7 versus sevoflurane: 33.7 pg/ml; p = 0.035) and attenuated the increase of IL-10 (Xenon: 127.9 versus sevoflurane: 548.3 pg/ml; p = 0.028). Both groups demonstrated a comparable intraoperative increase of oxidative stress (intra-OP: p = 0.29; post-OP: p = 0.65). While both groups showed an intraoperative increase of the cardioprotective mediators MIF and CXCL12/SDF-1α, only MIF levels decreased in the xenon group on the first postoperative day (50.0 ng/ml compared to 23.3 ng/ml; p = 0.012), whereas it remained elevated after sevoflurane anaesthesia (58.3 ng/ml to 53.6 ng/ml). Effects of patients' serum on chemotactic migration of peripheral mononuclear blood cells taken from healthy volunteers indicated a tendency towards enhanced migration after sevoflurane anaesthesia (p = 0.07). CONCLUSIONS: Compared to sevoflurane, balanced xenon anaesthesia triggers pro-inflammatory effects and suppresses the anti-inflammatory response in cardiac surgery patients even though the clinical significance remains unknown. TRIAL REGISTRATION: This clinical trial was approved by the European Medicines Agency (EudraCT-number: 2010-023942-63) and at ClinicalTrials.gov ( NCT01285271 ; first received: January 24, 2011).

Sevoflurane exposure prevents diaphragmatic oxidative stress during mechanical ventilation but reduces force and affects protein metabolism even during spontaneous breathing in a rat model.

BACKGROUND: Ventilator-induced diaphragmatic dysfunction is associated with the generation of oxidative stress, enhanced proteolysis, autophagy and reduced protein synthesis in the diaphragm. Sevoflurane is a common operating room anesthetic and can be used in the intensive care medicine as well. Besides its anesthetic properties, its use in cardiac ischemia-reperfusion models can maintain protein synthesis and inhibit generation of reactive oxygen species, if used at the beginning of heart surgery. This study has been performed on the hypothesis that sevoflurane might protect against ventilator-induced diaphragmatic dysfunction by preventing the production of oxidative stress. METHODS: Four-month-old, male Sprague-Dawley rats sedated with sevoflurane (minimal alveolar concentration = 1) were either mechanically ventilated (MV) for 12 hours (n = 8) or allowed to breathe spontaneously (SB) for 12 hours (n = 8). An acutely anesthetized group was used as a control (Con) group (n = 8). After euthanization, diaphragmatic contractile properties, fiber cross-sectional areas, proteolysis (calpain-1 and caspase-3), and oxidative stress (lipid peroxidation, protein oxidation) were examined. After testing for normality, 1-way or 2-way analysis of variance with the Dunnett post hoc test was used to test for significance. RESULTS: The diaphragm contractile force was similarly reduced at all stimulation frequencies in the SB and MV groups compared with controls. Markers of oxidative stress and fiber cross-sectional areas were unaltered between Con and SB/MV, respectively. The calcium-dependent proteases (calpain-1 and caspase-3) were enhanced in the MV group. The p-AKT/AKT ratio and p-FoxO1/FoxO1 ratio were significantly and similarly reduced after sevoflurane exposure in the SB and MV group compared with Con group. CONCLUSIONS: Exposure to sevoflurane did not induce oxidative stress. It led to reduction in diaphragmatic force. In the MV group, sevoflurane led to the activation of atrophy signaling pathways. These findings are of particular importance for clinical utilization in intensive care units and question its use, especially during the phases of SB.

Recovery of diaphragm function following mechanical ventilation in a rodent model.

BACKGROUND: Mechanical ventilation (MV) induces diaphragmatic muscle fiber atrophy and contractile dysfunction (ventilator induced diaphragmatic dysfunction, VIDD). It is unknown how rapidly diaphragm muscle recovers from VIDD once spontaneous breathing is restored. We hypothesized that following extubation, the return to voluntary breathing would restore diaphragm muscle fiber size and contractile function using an established rodent model. METHODS: Following 12 hours of MV, animals were either euthanized or, after full wake up, extubated and returned to voluntary breathing for 12 hours or 24 hours. Acutely euthanized animals served as controls (each n = 8/group). Diaphragmatic contractility, fiber size, protease activation, and biomarkers of oxidative damage in the diaphragm were assessed. RESULTS: 12 hours of MV induced VIDD. Compared to controls diaphragm contractility remained significantly depressed at 12 h after extubation but rebounded at 24 h to near control levels. Diaphragmatic levels of oxidized proteins were significantly elevated after MV (p = 0.002) and normalized at 24 hours after extubation. CONCLUSIONS: These findings indicate that diaphragm recovery from VIDD, as indexed by fiber size and contractile properties, returns to near control levels within 24 hours after returning to spontaneous breathing. Besides the down-regulation of proteolytic pathways and oxidative stress at 24 hours after extubation further repairing mechanisms have to be determined.