Individualised flow-controlled ventilation reduces applied mechanical power and improves ventilation efficiency in a porcine intra-abdominal hypertension model.

BACKGROUND: Aim of this study was to evaluate feasibility and effects of individualised flow-controlled ventilation (FCV), based on compliance guided pressure settings, compared to standard of pressure-controlled ventilation (PCV) in a porcine intra-abdominal hypertension (IAH) model. The primary aim of this study was to investigate oxygenation. Secondary aims were to assess respiratory and metabolic variables and lung tissue aeration. METHODS: Pigs were randomly assigned to FCV (n = 9) and PCV (n = 9). IAH was induced by insufflation of air into the abdomen to induce IAH grades ranging from 0 to 3. At each IAH grade FCV was undertaken using compliance guided pressure settings, or PCV (n = 9) was undertaken with the positive end-expiratory pressure titrated for maximum compliance and the peak pressure set to achieve a tidal volume of 7 ml/kg. Gas exchange, ventilator settings and derived formulas were recorded at two timepoints for each grade of IAH. Lung aeration was assessed by a computed tomography scan at IAH grade 3. RESULTS: All 18 pigs (median weight 54 kg [IQR 51-67]) completed the observation period of 4 h. Oxygenation was comparable at each IAH grade, but a significantly lower minute volume was required to secure normocapnia in FCV at all IAH grades (7.6 vs. 14.4, MD - 6.8 (95% CI - 8.5 to - 5.2) l/min; p < 0.001). There was also a significant reduction of applied mechanical power being most evident at IAH grade 3 (25.9 vs. 57.6, MD - 31.7 (95% CI - 39.7 to - 23.7) J/min; p < 0.001). Analysis of Hounsfield unit distribution of the computed tomography scans revealed a significant reduction in non- (5 vs. 8, MD - 3 (95% CI - 6 to 0) %; p = 0.032) and poorly-aerated lung tissue (7 vs. 15, MD - 6 (95% CI - 13 to - 3) %, p = 0.002) for FCV. Concomitantly, normally-aerated lung tissue was significantly increased (84 vs. 76, MD 8 (95% CI 2 to 15) %; p = 0.011). CONCLUSIONS: Individualised FCV showed similar oxygenation but required a significantly lower minute volume for CO2-removal, which led to a remarkable reduction of applied mechanical power. Additionally, there was a shift from non- and poorly-aerated lung tissue to normally-aerated lung tissue in FCV compared to PCV.

Flow-controlled versus pressure-controlled ventilation in cardiac surgery with cardiopulmonary bypass - A single-center, prospective, randomized, controlled trial.

STUDY OBJECTIVE: Multifactorial comparison of flow-controlled ventilation (FCV) to standard of pressure-controlled ventilation (PCV) in terms of oxygenation in cardiac surgery patients after chest closure. DESIGN: Prospective, non-blinded, randomized, controlled trial. SETTING: Operating theatre at an university hospital, Austria. PATIENTS: Patients scheduled for elective, open, on-pump, cardiac surgery. INTERVENTIONS: Participants were randomized to either individualized FCV (compliance guided end-expiratory and peak pressure setting) or control of PCV (compliance guided end-expiratory pressure setting and tidal volume of 6-8 ml/kg) for the duration of surgery. MEASUREMENTS: The primary outcome measure was oxygenation (PaO2/FiO2) 15 min after intraoperative chest closure. Secondary endpoints included CO2-removal assessed as required minute volume to achieve normocapnia and lung tissue aeration assessed by Hounsfield unit distribution in postoperative computed tomography scans. MAIN RESULTS: Between April 2020 and April 2021 56 patients were enrolled and 50 included in the primary analysis (mean age 70 years, 38 (76%) men). Oxygenation, assessed by PaO2/FiO2, was significantly higher in the FCV group (n = 24) compared to the control group (PCV, n = 26) (356 vs. 309, median difference (MD) 46 (95% CI 3 to 90) mmHg; p = 0.038). Additionally, the minute volume required to obtain normocapnia was significantly lower in the FCV group (4.0 vs. 6.1, MD -2.0 (95% CI -2.5 to -1.5) l/min; p < 0.001) and correlated with a significantly lower exposure to mechanical power (5.1 vs. 9.8, MD -5.1 (95% CI -6.2 to -4.0) J/min; p < 0.001). Evaluation of lung tissue aeration revealed a significantly reduced amount of non-aerated lung tissue in FCV compared to PCV (5 vs. 7, MD -3 (95% CI -4 to -1) %; p < 0.001). CONCLUSIONS: In patients undergoing on-pump, cardiac surgery individualized FCV significantly improved oxygenation and lung tissue aeration compared to PCV. In addition, carbon dioxide removal was accomplished at a lower minute volume leading to reduced applied mechanical power.

Improved ventilation efficiency due to continuous gas flow compared to decelerating gas flow in mechanical ventilation: results of a porcine trial.

In pressure-controlled ventilation (PCV), a decelerating gas flow pattern occurs during inspiration and expiration. In contrast, flow-controlled ventilation (FCV) guarantees a continuous gas flow throughout the entire ventilation cycle where the inspiration and expiration phases are simply performed by a change of gas flow direction. The aim of this trial was to highlight the effects of different flow patterns on respiratory variables and gas exchange. Anesthetized pigs were ventilated with either FCV or PCV for 1 h and thereafter for 30 min each in a crossover comparison. Both ventilation modes were set with a peak pressure of 15 cmH2O, positive end-expiratory pressure of 5 cmH2O, a respiratory rate of 20/min, and a fraction of inspired oxygen at 0.3. All respiratory variables were collected every 15 min. Tidal volume and respiratory minute volume were significantly lower in FCV (n = 5) compared with PCV (n = 5) animals [4.6 vs. 6.6, MD -2.0 (95% CI -2.6 to -1.4) mL/kg; P < 0.001 and 7.3 vs. 9.5, MD -2.2 (95% CI -3.3 to -1.0) L/min; P = 0.006]. Notwithstanding these differences, CO2-removal as well as oxygenation was not inferior in FCV compared with PCV. Mechanical ventilation with identical ventilator settings resulted in lower tidal volumes and consecutive minute volume in FCV compared with PCV. This finding can be explained physically by the continuous gas flow pattern in FCV that necessitates a lower alveolar pressure amplitude. Interestingly, gas exchange was comparable in both groups, which is suggestive of improved ventilation efficiency at a continuous gas flow pattern.NEW & NOTEWORTHY This study examined the effects of a continuous (flow-controlled ventilation, FCV) vs. decelerating (pressure-controlled ventilation, PCV) gas flow pattern during mechanical ventilation. It was shown that FCV necessitates a lower alveolar pressure amplitude leading to reduced applied tidal volumes and consequently minute volume. Notwithstanding these differences, CO2-removal as well as oxygenation was not inferior in FCV compared with PCV, which is suggestive of improved gas exchange efficiency at a continuous gas flow pattern.

Short time effects of compliance guided flow-controlled ventilation versus standard of care pressure-controlled ventilation: a prospective porcine trial.

BACKGROUND: Flow-controlled ventilation (FCV) represents a novel ventilation method, which guarantees a continuous gas flow during inspiration and expiration. Long term comparison to volume- and pressure-controlled ventilation (PCV) after five- and ten hours have shown improved gas exchange parameters and lung tissue aeration. Aim of this porcine trial was to compare gas exchange parameters and lung tissue aeration in short time application of FCV compared to PCV to determine effects which will most probably pertain in short lasting procedures under general anesthesia. METHODS: After induction of general anesthesia nine pigs were randomly ventilated either with compliance guided FCV settings or standard of PCV with compliance titrated positive end-expiratory pressure and peak pressure set to achieve a tidal volume of 7 mL/kg. Subsequently an arterial blood gas sample was obtained, and a computed tomography scan was performed. Afterwards, each animal was extubated and on the following day the same protocol was performed again with the alternative ventilation method. RESULTS: Primary analysis of 18 datasets from nine animals (with paired comparison) revealed a significantly improved oxygenation with FCV compared to control (paO2 118 vs. 109, 95% CI 2 to 16 mm Hg; P=0.042). The required respiratory minute volume was significantly lower with FCV (7.4 vs. 10.8, 95% CI -4.0 to -2.9 L/min; P<0.001) to achieve similar levels of normocapnia. However, lung tissue aeration did not significantly differ between ventilation methods. CONCLUSIONS: In this short-term ventilation comparison FCV improved gas exchange parameters without differences in lung tissue aeration compared to PCV.

Individualised flow-controlled versus pressure-controlled ventilation in a porcine oleic acid-induced acute respiratory distress syndrome model.

BACKGROUND: A continuous gas flow provided by flow-controlled ventilation (FCV) facilitates accurate dynamic compliance measurement and allows the clinician to individually optimise positive end-expiratory and peak pressure settings accordingly. OBJECTIVE: The aim of this study was to compare the efficiency of gas exchange and impact on haemodynamics between individualised FCV and pressure-controlled ventilation (PCV) in a porcine model of oleic acid-induced acute respiratory distress syndrome (ARDS). DESIGN: Randomised controlled interventional trial conducted on 16 pigs. SETTING: Animal operating facility at the Medical University Innsbruck. INTERVENTIONS: ARDS was induced in lung healthy pigs by intravenous infusion of oleic acid until moderate-to-severe ARDS at a stable Horowitz quotient (PaO 2 FiO 2-1 ) of 80 to 120 over a period of 30 min was obtained. Ventilation was then either performed with individualised FCV ( n  = 8) established by compliance-guided pressure titration or PCV ( n  = 8) with compliance-guided titration of the positive end-expiratory pressure and peak pressure set to achieve a tidal volume of 6 ml kg -1 over a period of 2 h. MAIN OUTCOME MEASURES: Gas exchange parameters were assessed by the PaO 2 FiO 2-1 quotient and CO 2 removal by the PaCO 2 value in relation to required respiratory minute volume. Required catecholamine support for haemodynamic stabilisation was measured. RESULTS: The FCV group showed significantly improved oxygenation [149.2 vs. 110.4, median difference (MD) 38.7 (8.0 to 69.5) PaO 2 FiO 2-1 ; P  = 0.027] and CO 2 removal [PaCO 2 7.25 vs. 9.05, MD -1.8 (-2.87 to -0.72) kPa; P  = 0.006] at a significantly lower respiratory minute volume [8.4 vs. 11.9, MD -3.6 (-5.6 to -1.5) l min -1 ; P  = 0.005] compared with PCV. In addition, in FCV-pigs, haemodynamic stabilisation occurred with a significant reduction of required catecholamine support [norepinephrine 0.26 vs. 0.86, MD -0.61 (-1.12 to -0.09) µg kg -1  min -1 ; P  = 0.037] during 2 ventilation hours. CONCLUSION: In this oleic acid-induced porcine ARDS model, individualised FCV significantly improved gas exchange and haemodynamic stability compared with PCV. TRIAL REGISTRATION: Protocol no.: BMBWF-66.011/0105-V/3b/2019).

A review of the therapeutic management of ulcerative colitis.

Ulcerative colitis (UC) is a chronic relapsing and remitting gastrointestinal disorder of uncertain aetiology. The last two decades have seen an expansion in the therapeutic arsenal used to treat UC. This has resulted in improved clinical remission and response rates. Nonetheless, staples in our current medical management originate from trials conducted in the early 20th century. In this review article, we aim to outline the key milestones in the history of the medical management of UC in addition to highlighting promising therapeutic developments for the future.

Individualised flow-controlled ventilation versus pressure-controlled ventilation in a porcine model of thoracic surgery requiring one-lung ventilation: A laboratory study.

BACKGROUND: Flow-controlled ventilation (FCV) enables precise determination of dynamic compliance due to a continuous flow coupled with direct tracheal pressure measurement. Thus, pressure settings can be adjusted accordingly in an individualised approach. OBJECTIVE: The aim of this study was to compare gas exchange of individualised FCV to pressure-controlled ventilation (PCV) in a porcine model of simulated thoracic surgery requiring one-lung ventilation (OLV). DESIGN: Controlled interventional trial conducted on 16 domestic pigs. SETTING: Animal operating facility at the Medical University of Innsbruck. INTERVENTIONS: Thoracic surgery was simulated with left-sided thoracotomy and subsequent collapse of the lung over a period of three hours. When using FCV, ventilation was performed with compliance-guided pressure settings. When using PCV, end-expiratory pressure was adapted to achieve best compliance with peak pressure adjusted to achieve a tidal volume of 6 ml kg -1 during OLV. MAIN OUTCOME MEASURES: Gas exchange was assessed by the Horowitz index (= P aO 2 /FIO 2 ) and CO 2 removal by the P aCO 2 value in relation to required respiratory minute volume. RESULTS: In the FCV group ( n  = 8) normocapnia could be maintained throughout the OLV trial despite a significantly lower respiratory minute volume compared to the PCV group ( n  = 8) (8.0 vs. 11.6, 95% confidence interval, CI -4.5 to -2.7 l min -1 ; P  < 0.001), whereas permissive hypercapnia had to be accepted in PCV ( P aCO 2 5.68 vs. 6.89, 95% CI -1.7 to -0.7 kPa; P  < 0.001). The Horowitz index was comparable in both groups but calculated mechanical power was significantly lower in FCV (7.5 vs. 22.0, 95% CI -17.2 to -11.8 J min -1 ; P  < 0.001). CONCLUSIONS: In this porcine study FCV maintained normocapnia during OLV, whereas permissive hypercapnia had to be accepted in PCV despite a substantially higher minute volume. Reducing exposure of the lungs to mechanical power applied by the ventilator in FCV offers a possible advantage for this mode of ventilation in terms of lung protection.

Energy dissipation during expiration and ventilator-induced lung injury: an experimental animal study.

The amount of energy delivered to the respiratory system is recognized as a cause of ventilator-induced lung injury (VILI). How energy dissipation within the lung parenchyma causes damage is still a matter of debate. Expiratory flow control has been proposed as a strategy to reduce the energy dissipated into the respiratory system during expiration and, possibly, VILI. We studied 22 healthy pigs (29 ± 2 kg), which were randomized into a control (n = 11) and a valve group (n = 11), where the expiratory flow was controlled through a variable resistor. Both groups were ventilated with the same tidal volume, positive end-expiratory pressure (PEEP), and inspiratory flow. Electric impedance tomography was continuously acquired. At completion, lung weight, wet-to-dry ratios, and histology were evaluated. The total mechanical power was similar in the control and valve groups (8.54 ± 0.83 J·min-1 and 8.42 ± 0.54 J·min-1, respectively, P = 0.552). The total energy dissipated within the whole system (circuit + respiratory system) was remarkably different (4.34 ± 0.66 vs. 2.62 ± 0.31 J/min, P < 0.001). However, most of this energy was dissipated across the endotracheal tube (2.87 ± 0.3 vs. 1.88 ± 0.2 J/min, P < 0.001). The amount dissipated into the respiratory system averaged 1.45 ± 0.5 in controls versus 0.73 ± 0.16 J·min-1 in the valve group, P < 0.001. Although respiratory mechanics, gas exchange, hemodynamics, wet-to-dry ratios, and histology were similar in the two groups, the decrease of end-expiratory lung impedance was significantly greater in the control group (P = 0.02). We conclude that with our experimental conditions, the reduction of energy dissipated in the respiratory system did not lead to appreciable differences in VILI.NEW & NOTEWORTHY Energy dissipation within the respiratory system is a factor promoting ventilator-induced lung injury (VILI). In this animal study, we modulated the expiratory flow, reducing the energy dissipated in the system. However, this reduction happened mostly across the endotracheal tube, and only partly in the respiratory system. Therefore, in healthy lungs, the advantage in energy dissipation does not reduce VILI, but the advantages might be more relevant in diseased lungs under injurious ventilation.

Individualized flow-controlled ventilation compared to best clinical practice pressure-controlled ventilation: a prospective randomized porcine study.

BACKGROUND: Flow-controlled ventilation is a novel ventilation method which allows to individualize ventilation according to dynamic lung mechanic limits based on direct tracheal pressure measurement at a stable constant gas flow during inspiration and expiration. The aim of this porcine study was to compare individualized flow-controlled ventilation (FCV) and current guideline-conform pressure-controlled ventilation (PCV) in long-term ventilation. METHODS: Anesthetized pigs were ventilated with either FCV or PCV over a period of 10 h with a fixed FiO2 of 0.3. FCV settings were individualized by compliance-guided positive end-expiratory pressure (PEEP) and peak pressure (Ppeak) titration. Flow was adjusted to maintain normocapnia and the inspiration to expiration ratio (I:E ratio) was set at 1:1. PCV was performed with a PEEP of 5 cm H2O and Ppeak was set to achieve a tidal volume (VT) of 7 ml/kg. The respiratory rate was adjusted to maintain normocapnia and the I:E ratio was set at 1:1.5. Repeated measurements during observation period were assessed by linear mixed-effects model. RESULTS: In FCV (n = 6), respiratory minute volume was significantly reduced (6.0 vs 12.7, MD - 6.8 (- 8.2 to - 5.4) l/min; p < 0.001) as compared to PCV (n = 6). Oxygenation was improved in the FCV group (paO2 119.8 vs 96.6, MD 23.2 (9.0 to 37.5) Torr; 15.97 vs 12.87, MD 3.10 (1.19 to 5.00) kPa; p = 0.010) and CO2 removal was more efficient (paCO2 40.1 vs 44.9, MD - 4.7 (- 7.4 to - 2.0) Torr; 5.35 vs 5.98, MD - 0.63 (- 0.99 to - 0.27) kPa; p = 0.006). Ppeak and driving pressure were comparable in both groups, whereas PEEP was significantly lower in FCV (p = 0.002). Computed tomography revealed a significant reduction in non-aerated lung tissue in individualized FCV (p = 0.026) and no significant difference in overdistended lung tissue, although a significantly higher VT was applied (8.2 vs 7.6, MD 0.7 (0.2 to 1.2) ml/kg; p = 0.025). CONCLUSION: Our long-term ventilation study demonstrates the applicability of a compliance-guided individualization of FCV settings, which resulted in significantly improved gas exchange and lung tissue aeration without signs of overinflation as compared to best clinical practice PCV.

Vedolizumab in the treatment of inflammatory bowel disease: evolving paradigms.

Inflammatory bowel diseases, comprising Crohn's disease (CD) and ulcerative colitis (UC), are chronic, relapsing and remitting immune-mediated inflammatory diseases affecting the gastrointestinal tract. Vedolizumab is the first licensed drug in a group of 'gut-selective' biological agents used to treat inflammatory bowel diseases. The GEMINI registrational trials established the efficacy of vedolizumab for the induction and maintenance of remission in both CD and UC, with the most favourable results in tumour necrosis factor (TNF)-antagonist-naive patients. In recent years, a wealth of 'real-world' data has emerged supporting positive clinical, endoscopic and histological outcomes in patients treated with vedolizumab (VDZ) as well as reassuring safety data. More recently, the results of the first head-to-head trials of VDZ and TNF antagonists have been reported, as well as the results of a number of studies exploring the role of therapeutic drug monitoring with VDZ. This review brings together data reported on VDZ to date, including from the GEMINI trials, real-world data and emerging studies regarding therapeutic drug monitoring and immunogenicity. The safety profile of VDZ is also reviewed. Evolving treatment paradigms are explored, including data regarding the role of VDZ in perianal CD, post-operative complications and recurrence, extraintestinal manifestations and pregnancy.

Flow-controlled ventilation during ear, nose and throat surgery: A prospective observational study.

BACKGROUND: Flow-controlled ventilation (FCV) is a new mechanical ventilation mode that maintains constant flow during inspiration and expiration with standard tidal volumes via cuffed narrow-bore endotracheal tubes. Originating in manually operated 'expiratory ventilation assistance', FCV extends this technique by automatic control of airway flow, monitoring of intratracheal pressure and control of peak inspiratory pressure and end-expiratory pressure. FCV has not yet been described in a clinical study. OBJECTIVE: The aim of this study was to provide an initial assessment of FCV in mechanically ventilated patients undergoing ear, nose and throat surgery and evaluate its potential for future use. DESIGN: An observational study. SETTING: Two German academic medical centres from 24 November 2017 to 09 January 2018. PATIENTS: Consecutive patients (≥ 18 years) scheduled for elective ear, nose and throat surgery. Exclusion criteria were planned laser surgery, intended fibreoptic awake intubation, emergency procedures, increased risk of aspiration, American Society of Anesthesiologists (ASA) physical status more than III and chronic obstructive pulmonary disease classified as GOLD stage more than II. INTERVENTION: Peri-operative use of FCV provided by a new type of ventilator (Evone) via a narrow-bore endotracheal tube (Tritube). MAIN OUTCOME MEASURES: Minute volume, respiratory rate, intratidal tracheal pressure amplitude (Δp) and end-tidal CO2 (PetCO2) were recorded every 5 min. All adverse events were noted. Data are presented as median [IQR]. RESULTS: Sixteen patients provided 15 evaluable data sets. A minute volume of 5.0 [4.4 to 6.4] l min and a respiratory rate of 9 [8 to 11] min generated a PetCO2 of 4.9 [4.8 to 5.0] kPa. Δp was 10 [9 to 12] cmH2O. Five adverse events were recorded: a tube obstruction due to airway secretions and four tube dislocations (two attributed to coughing, two not study-related). CONCLUSION: FCV achieves adequate PetCO2 levels with minute volume and Δp in the normal range. Tritube's high flow resistance may increase the likelihood of tube dislocations if the patient coughs. Although further evaluation is necessary, FCV provides a new option for short-term mechanical ventilation. The successful operation of FCV with narrow-bore tubes contributes to the armamentarium for airway management. TRIAL REGISTRATION: DRKS00013312.

Minimisation of dissipated energy in the airways during mechanical ventilation by using constant inspiratory and expiratory flows - Flow-controlled ventilation (FCV).

It has been suggested that energy dissipation in the airways during mechanical ventilation is associated with an increased probability of ventilator induced lung injury (VILI). We hypothesise that energy dissipation in the airways may be minimised by ventilating with constant flow during both the inspiration and expiration phases of the respiratory cycle. We present a simple analysis and numerical calculations that support our hypothesis and show that for ventilation with minimum dissipated energy not only should the flows during inspiration and expiration be controlled to be constant and continuous, but the ventilation should also be undertaken with an I:E ratio that is close to 1:1.

Parasite-derived plasma microparticles contribute significantly to malaria infection-induced inflammation through potent macrophage stimulation.

There is considerable debate as to the nature of the primary parasite-derived moieties that activate innate pro-inflammatory responses during malaria infection. Microparticles (MPs), which are produced by numerous cell types following vesiculation of the cellular membrane as a consequence of cell death or immune-activation, exert strong pro-inflammatory activity in other disease states. Here we demonstrate that MPs, derived from the plasma of malaria infected mice, but not naive mice, induce potent activation of macrophages in vitro as measured by CD40 up-regulation and TNF production. In vitro, these MPs induced significantly higher levels of macrophage activation than intact infected red blood cells. Immunofluorescence staining revealed that MPs contained significant amounts of parasite material indicating that they are derived primarily from infected red blood cells rather than platelets or endothelial cells. MP driven macrophage activation was completely abolished in the absence of MyD88 and TLR-4 signalling. Similar levels of immunogenic MPs were produced in WT and in TNF(-/-), IFN-gamma(-/-), IL-12(-/-) and RAG-1(-/-) malaria-infected mice, but were not produced in mice injected with LPS, showing that inflammation is not required for the production of MPs during malaria infection. This study therefore establishes parasitized red blood cell-derived MPs as a major inducer of systemic inflammation during malaria infection, raising important questions about their role in severe disease and in the generation of adaptive immune responses.