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AbstractPatients with COPD using long-term oxygen therapy (LTOT) over 15 h per day have improved outcomes. As inhalation of dry cold gas is detrimental to mucociliary clearance, humidified nasal high flow (NHF) oxygen may reduce frequency of exacerbations, while improving lung function and quality of life in this cohort. In this randomised crossover study, we assessed short-term physiological responses to NHF therapy in 30 males chronically treated with LTOT. LTOT (2–4 L/min) through nasal cannula was compared with NHF at 30 L/min from an AIRVO through an Optiflow nasal interface with entrained supplemental oxygen. Comparing NHF with LTOT: transcutaneous carbon dioxide (TcCO2) (43.3 vs 46.7 mm Hg, p<0.001), transcutaneous oxygen (TcO2) (97.1 vs 101.2 mm Hg, p=0.01), I:E ratio (0.75 vs 0.86, p=0.02) and respiratory rate (RR) (15.4 vs 19.2 bpm, p<0.001) were lower; and tidal volume (Vt) (0.50 vs 0.40, p=0.003) and end-expiratory lung volume (EELV) (174% vs 113%, p<0.001) were higher. EELV is expressed as relative change from baseline (%Δ). Subjective dyspnoea and interface comfort favoured LTOT. NHF decreased TcCO2, I:E ratio and RR, with a concurrent increase in EELV and Vt compared with LTOT. This demonstrates a potential mechanistic rationale behind the improved outcomes observed in long-term treatment with NHF in oxygen-dependent patients.Trial registration numberACTRN12613000028707.

Introduction Vital drugs may be degraded or sequestered in extracorporeal membrane oxygenation (ECMO) circuits, with lipophilic drugs considered to be particularly vulnerable. However, the circuit effects on protein-bound drugs have not been fully elucidated. The aim of this experimental study was to investigate the influence of plasma protein binding on drug disposition in ex vivo ECMO circuits. Methods Four identical ECMO circuits comprising centrifugal pumps and polymethylpentene oxygenators and were used. The circuits were primed with crystalloid, albumin and fresh human whole blood and maintained at a physiological pH and temperature for 24 hours. After baseline sampling, known quantities of study drugs (ceftriaxone, ciprofloxacin, linezolid, fluconazole, caspofungin and thiopentone) were injected into the circuit to achieve therapeutic concentrations. Equivalent doses of these drugs were also injected into four polypropylene jars containing fresh human whole blood for drug stability testing. Serial blood samples were collected from the controls and the ECMO circuits over 24 hours, and the concentrations of the study drugs were quantified using validated chromatographic assays. A regression model was constructed to examine the relationship between circuit drug recovery as the dependent variable and protein binding and partition coefficient (a measure of lipophilicity) as explanatory variables. Results Four hundred eighty samples were analysed. There was no significant loss of any study drugs in the controls over 24 hours. The average drug recoveries from the ECMO circuits at 24 hours were as follows: ciprofloxacin 96%, linezolid 91%, fluconazole 91%, ceftriaxone 80%, caspofungin 56% and thiopentone 12%. There was a significant reduction of ceftriaxone ( P = 0.01), caspofungin ( P = 0.01) and thiopentone ( P = 0.008) concentrations in the ECMO circuit at 24 hours. Both protein binding and partition coefficient were highly significant, with the model possessing a high coefficient of determination ( R 2  = 0.88, P <0.001). Conclusions Recovery of the highly protein-bound drugs ceftriaxone, caspofungin and thiopentone was significantly lower in the ECMO circuits at 24 hours. For drugs with similar lipophilicity, the extent of protein binding may determine circuit drug loss. Future clinical population pharmacokinetic studies should initially be focused on drugs with greater lipophilicity and protein binding, and therapeutic drug monitoring should be strongly considered with the use of such drugs.

ObjectiveTo determine the proportion of patients surviving their cardiac surgery who experienced non-home discharge (NHD) over a 16-year period in Australia and New Zealand (ANZ).DesignRetrospective, multicentre, cross-sectional study over the time period 01 January 2004 to 31 December 2019.SettingAdult patients who underwent cardiac surgery from the Australia New Zealand Intensive Care Society Adult Patient Database (APD).ParticipantsAdult patients (age 18 and above) who underwent index coronary artery bypass grafting, cardiac valve surgery or combined valve/coronary surgery.ExposureThe primary exposure variable was the calendar year during the which the index surgery was performed.OutcomeThe primary outcome was NHD after the index surgery. NHD included discharge to locations such as nursing home, chronic care facility, rehabilitation and palliative care.ResultsWe analysed 252 924 index cardiac surgical admissions from 101 discrete sites with a median age of 68 years (IQR 60–76), of which 74.2% (187 662 out of 252 920) were males. Of these, 4302 (1.7%) patients died in hospital and 213 011 (84.2%) were discharged home, 18 010 (7.1%) were transferred to another hospital and 17 601 (7%) experienced NHD. In Australia, 14 457 (6.4%) of patients progressed to NHD, compared with 3144 (11.7%) in New Zealand. The rate of NHD increased significantly over time (adjusted OR per year=1.06, 95% CI, 1.06 to 1.07, p<0.001). Increasing age, female sex, non-elective surgery, surgery type and Acute Physiology and Chronic Health Evaluation III Score were all associated with significant increase in NHD.ConclusionsThere was significant increase in NHD after cardiac surgery over time in ANZ. This has significant clinical relevance for informed consent discussions between healthcare providers and patients, and for healthcare services planning.

Background Sepsis is a multi-system syndrome that remains the leading cause of mortality and critical illness worldwide, with hemodynamic support being one of the cornerstones of the acute management of sepsis. We used an ovine model of endotoxemic shock to determine if 0.9% saline resuscitation contributes to lung inflammation and injury in acute respiratory distress syndrome, which is a common complication of sepsis, and investigated the potential role of matrix metalloproteinases in this process. Methods Endotoxemic shock was induced in sheep by administration of an escalating dose of lipopolysaccharide, after which they subsequently received either no fluid bolus resuscitation or a 0.9% saline bolus. Lung tissue, bronchoalveolar fluid (BAL) and plasma were analysed by real-time PCR, ELISA, flow cytometry and immunohistochemical staining to assess inflammatory cells, cytokines, hyaluronan and matrix metalloproteinases. Results Endotoxemia was associated with decreased serum albumin and total protein levels, with activated neutrophils, while the glycocalyx glycosaminoglycan hyaluronan was significantly increased in BAL. Quantitative real-time PCR studies showed higher expression of IL-6 and IL-8 with saline resuscitation but no difference in matrix metalloproteinase expression. BAL and tissue homogenate levels of IL-6, IL-8 and IL-1β were elevated. Conclusions This data shows that the inflammatory response is enhanced when a host with endotoxemia is resuscitated with saline, with a comparatively higher release of inflammatory cytokines and endothelial/glycocalyx damage, but no change in matrix metalloproteinase levels.

Background Patients who require positive pressure ventilation through a tracheostomy are unable to phonate due to the inflated tracheostomy cuff. Whilst a speaking valve (SV) can be used on a tracheostomy tube, its use in ventilated ICU patients has been inhibited by concerns regarding potential deleterious effects to recovering lungs. The objective of this study was to assess end expiratory lung impedance (EELI) and standard bedside respiratory parameters before, during and after SV use in tracheostomised patients weaning from mechanical ventilation. Methods A prospective observational study was conducted in a cardio-thoracic adult ICU. 20 consecutive tracheostomised patients weaning from mechanical ventilation and using a SV were recruited. Electrical Impedance Tomography (EIT) was used to monitor patients’ EELI. Changes in lung impedance and standard bedside respiratory data were analysed pre, during and post SV use. Results Use of in-line SVs resulted in significant increase of EELI. This effect grew and was maintained for at least 15 minutes after removal of the SV ( p < 0.001 ). EtCO 2 showed a significant drop during SV use (p = 0.01) whilst SpO 2 remained unchanged. Respiratory rate (RR (breaths per minute)) decreased whilst the SV was in situ ( p <0.001 ), and heart rate (HR (beats per minute)) was unchanged. All results were similar regardless of the patients’ respiratory requirements at time of recruitment. Conclusions In this cohort of critically ill ventilated patients, SVs did not cause derecruitment of the lungs when used in the ventilator weaning period. Deflating the tracheostomy cuff and restoring the airflow via the upper airway with a one-way valve may facilitate lung recruitment during and after SV use, as indicated by increased EELI. Trial registration Anna-Liisa Sutt, Australian New Zealand Clinical Trials Registry (ANZCTR). ACTRN: ACTRN12615000589583 . 4/6/2015.

Surgical aortic valve replacement (AVR) is the standard of care for severe aortic valve disease; however, post-operative complications continue to pose challenges. Inflammation caused by increased release of cell-free mitochondrial DNA (cf-mtDNA) during surgery may be a contributing factor. The aim of this pilot study was to investigate the relationship between cf-mtDNA release and the risk of inflammatory-mediated post-operative complications in adult AVR patients. Plasma was collected from patients undergoing an AVR with cardiopulmonary bypass (CPB) at baseline, intra-operatively and post ICU admission at 6, 12 and 18 h. Cf-mtDNA was quantified and inflammatory biomarker expression in leukocytes and plasma was assessed. Cf-mtDNA levels increased 16-fold at the end of CPB with a corresponding increase in average fragment size. Cf-mtDNA levels may be associated with post-operative bleeding, infection, hepatic failure and hospital length of stay. Gene expression and plasma analysis revealed altered levels of markers associated with inflammation and innate immune responses. Several markers were associated with post-operative complications and outcomes. Our results indicate that cf-mtDNA levels, including average fragment sizes, are increased following initiation of CPB in AVR patients, and may be associated with post-operative complications and outcomes. However, larger studies are needed to validate these findings.

IntroductionExtracorporeal membrane oxygenation (ECMO) provides cardiac and/or respiratory support when other therapies fail. Nosocomial infection is reported in up to 64% of patients receiving ECMO and increases morbidity and mortality. These patients are at high risk of infection due, in part, to the multiple invasive devices required in their management, the largest being the cannulae through which ECMO is delivered. Prevalence of nosocomial infection in ECMO patients, including ECMO cannula-related infection, is not well described across Australia and New Zealand.Methods and analysisThis is a prospective, observational point prevalence study of 12 months duration conducted at 11 ECMO centres across Australia and New Zealand. Data will be collected for every patient receiving ECMO during 12 predetermined data collection weeks. The primary outcome is the prevalence of laboratory-confirmed bloodstream infection, and suspected or probable nosocomial infections; and the secondary outcomes include describing ECMO cannula dressing and securement practices, and adherence to local dressing and securement guidelines. Data collection will be finalised by March 2019.Ethics and disseminationRelevant ethical and governance approvals have been received. Study results will describe the prevalence of suspected and confirmed nosocomial infection in adult, paediatric and neonatal patients receiving ECMO across Australia and New Zealand. It is expected that the results will be hypothesis generating and lead to interventional trials aimed at reducing the high infection rates seen in this cohort. Results will be published in peer-reviewed journals and presented at relevant conferences.Trial registration numberANZCTRN12618001109291; Pre-results.

Speaking valves (SV) are used infrequently in tracheostomised ICU patients due to concerns regarding their putative effect on lung recruitment. A recent study in cardio-thoracic population demonstrated increased end-expiratory lung volumes during and post SV use without examining if the increase in end-expiratory lung impedance (EELI) resulted in alveolar recruitment or potential hyperinflation in discrete loci. A secondary analysis of Electrical Impedance Tomography (EIT) data from a previous study was conducted. EELI distribution and tidal variation (TV) were assessed with a previously validated tool. A new tool was used to investigate ventilated surface area (VSA) and regional ventilation delay (RVD) as indicators of alveolar recruitment. The increase in EELI was found to be uniform with significant increase across all lung sections (p<0.001). TV showed an initial non-significant decrease (p=0.94) with subsequent increase significantly above baseline (p<0.001). VSA and RVD showed non-significant changes during and post SV use. These findings indicate that hyperinflation did not occur with SV use, which is supported by previously published data on respiratory parameters. These data along with obvious psychological benefits to patients are encouraging towards safe use of SVs in this critically ill cardio-thoracic patient population. Trial registration: Anna-Liisa Sutt, Australian New Zealand Clinical Trials Registry (ANZCTR). ACTRN: ACTRN12615000589583. 4/6/2015. •Uniform increase of end-expiratory lung volume across ventral-dorsal and R-L lung sections with speaking valve use.•Data suggests no alveolar hyperinflation associated with speaking valve use.•Data are encouraging towards wide use of speaking valves in intensive care.

Introduction: Oxygenation and carbon dioxide removal during venoarterial extracorporeal membrane oxygenation (VA ECMO) depend on a complex interplay of ECMO blood and gas flows, native lung and cardiac function as well as the mechanical ventilation strategy applied. Objective: To determine the association of oxygenation, carbon dioxide removal, and mechanical ventilation practices with in-hospital mortality in patients who received VA ECMO. Methods: Single center, retrospective cohort study. All consecutive patients who received VA ECMO in a tertiary ECMO referral center over a 5-year period were included. Data on demographics, ECMO and ventilator support details, and blood gas parameters for the duration of ECMO were collected. A multivariable logistic time-series regression model with in-hospital mortality as the primary outcome variable was used to analyse the data with significant factors at the univariate level entered into the multivariable regression model. Results: Overall, 52 patients underwent VA ECMO: 26/52 (50%) survived to hospital discharge. The median PaO 2 for the duration of ECMO support was 146 mmHg [IQR 131–188] and PaCO 2 was 37.2 mmHg [IQR 35.3, 39.9]. Patients who survived to hospital discharge had a significantly lower median PaO 2 (117 [98, 140] vs. 154 [105, 212] mmHg, P = 0.04) and higher median PaCO 2 (38.3 [36.1, 41.1] vs. 36.3 [34.5, 37.8] mmHg, p = 0.03). Survivors also had significantly lower median VA ECMO blood flow rate (EBFR, 3.6 [3.3, 4.2] vs. 4.3 [3.8, 5.2] L/min, p = < 0.001) and greater measured minute ventilation (7.04 [5.63, 8.35] vs. 5.32 [4.43, 6.83] L/min, p = 0.01). EBFR, PaO 2 , PaCO 2 , and minute ventilation, however, were not independently associated with death in a multivariable analysis. Conclusion: This exploratory analysis in a small group of VA ECMO supported patients demonstrated that hyperoxemia was common during VA ECMO but was not independently associated with increased mortality. Survivors also received lower EBFR and had greater minute ventilation, but this was also not independently associated with survival. These findings highlight that interactions between EBFR, PaO 2 , and native lung ventilation may be more relevant than their individual association with survival. Further research is indicated to determine the optimal ECMO and ventilator settings on outcomes in VA ECMO.

BackgroundPatients with severe acute respiratory distress syndrome (ARDS) typically receive ultra-protective ventilation after extracorporeal membrane oxygenation (ECMO) is initiated. While the benefit of ECMO appears to derive from supporting “lung rest”, reductions in the intensity of mechanical ventilation, principally tidal volume limitation, may manifest radiologically. This study evaluated the relative changes in radiographic assessment of lung edema (RALE) score upon venovenous ECMO initiation in patients with severe ARDS.MethodsDigital chest x-rays (CXR) performed at baseline immediately before initiation of ECMO, and at intervals post (median 1.1, 2.1, and 9.6 days) were reviewed in 39 Adult ARDS patients. One hundred fifty-six digital images were scored by two independent, blinded radiologists according to the RALE (Radiographic Assessment of Lung Edema) scoring criteria. Ventilatory data, ECMO parameters and fluid balance were recorded at corresponding time points. Multivariable analysis was performed analyzing the change in RALE score over time relative to baseline.ResultsThe RALE score demonstrated excellent inter-rater agreement in this novel application in an ECMO cohort. Mean RALE scores increased from 28 (22–37) at baseline to 35 (26–42) ( p < 0.001) on D1 of ECMO; increasing RALE was associated with higher baseline APACHE III scores [ß value +0.19 (0.08, 0.30) p = 0.001], and greater reductions in tidal volume [ß value −2.08 (−3.07, −1.10) p < 0.001] after ECMO initiation. Duration of mechanical ventilation, and ECMO support did not differ between survivors and non-survivors.ConclusionsThe magnitude of reductions in delivered tidal volumes correlated with increasing RALE scores (radiographic worsening) in ARDS patients receiving ECMO. Implications for patient centered outcomes remain unclear. There is a need to define appropriate ventilator settings on venovenous ECMO, counterbalancing the risks vs. benefits of optimal “lung rest” against potential atelectrauma.