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INTRODUCTION: Organs procured following brain stem death (BSD) are the main source of organ grafts for transplantation. However, BSD is associated with inflammatory responses that may damage the organ and affect both the quantity and quality of organs available for transplant. Therefore, we aimed to investigate plasma and bronchoalveolar lavage (BAL) pro-inflammatory cytokine profiles and cardiovascular physiology in a clinically relevant 6-hour ovine model of BSD. METHODS: Twelve healthy female sheep (37‒42 Kg) were anaesthetized and mechanically ventilated prior to undergoing BSD induction and then monitored for 6 hours. Plasma and BAL endothelin-1 and cytokines (IL-1β, 6, 8 and tumour necrosis factor alpha (TNF-α)) were assessed by ELISA. Differential white blood cell counts were performed. Cardiac function during BSD was also examined using echocardiography, and cardiac biomarkers (A-type natriuretic peptide and troponin I were measured in plasma. RESULTS: Plasma concentrations big ET-1, IL-6, IL-8, TNF-α and BAL IL-8 were significantly (p < 0.01) increased over baseline at 6 hours post-BSD. Increased numbers of neutrophils were observed in the whole blood (3.1×109 cells/L [95% confidence interval (CI) 2.06 - 4.14] vs. 6×109 cells/L [95%CI 3.92 - 7.97]; p < 0.01) and BAL (4.5×109 cells/L [95%CI 0.41 - 9.41] vs. 26 [95%CI 12.29 - 39.80]; p=0.03) after 6 hours of BSD induction vs baseline. A significant increase in ANP production (20.28 pM [95%CI 16.18 - 24.37] vs. 78.68 pM [95%CI 53.16 - 104.21];p < 0.0001) and cTnI release (0.039 ng/mL vs. 4.26 [95%CI 2.69 - 5.83] ng/mL; p < 0.0001), associated with a significant reduction in heart contractile function, were observed between baseline and 6 hours. CONCLUSIONS: BSD induced systemic pro-inflammatory responses, characterized by increased neutrophil infiltration and cytokine production in the circulation and BAL fluid, and associated with reduced heart contractile function in ovine model of BSD.

Purpose Cold static storage (CSS) is the standard method for heart preservation during transplantation (HTx). However, CSS beyond 4 hours increases the risk of primary graft dysfunction (PGD). Hypothermic ex vivo perfusion (HEVP) of donor hearts allows oxygen delivery during preservation, and may facilitate extended donor preservation without increasing PGD risk. We compared post-HTx survival, systemic inflammation and cardiac function following donor heart preservation by CSS (2 hrs) versus HEVP (2 and 8 hrs). Methods Brain death was induced in donor sheep for 24 hrs. Donor hearts were preserved by a) CSS for 2 hrs (n=7), b) HEVP for 2 hrs (n=4), or c) HEVP for 8 hrs (n=4). Orthotopic HTx was performed in matched recipients. Recipients were weaned from cardiopulmonary bypass and monitored for 6 hrs. Recipient blood was collected and assayed for inflammatory cytokines and cardiac markers. Cardiac function was assessed by echocardiography. Results Six-hour survival was 71% following CSS, and 100% following 2 and 8 hrs HEVP, respectively. Recipients systemic interleukin-6 and 8 levels were reduced using HEVP vs CSS. Post-HTx haemodynamic function was no different between groups, but HEVP reduced the requirement for vasoactive support compared to CSS (2 hrs CSS: 1.57±0.7; 2 hrs HEVP: 0.35±0.09; 8 hrs HEVP: 0.35±0.05 mmHg−1). HEVP was associated with reduced post-HTx lactate (2 hrs CSS: 11.4±1.8; 2 hrs HEVP: 5.2±0.7; 8 hrs HEVP: 6.7±1.3 mmol/L), more stable base excess and physiological pH in blood. Post-HTx cardiac function was no different between groups. Cardiac troponin I levels were comparable between CSS vs. 8 hrs HEVP, but reduced with 2 hrs HEVP. Conclusion Preliminary data on donor heart preservation by HEVP shows promising outcomes in comparison to CSS. Heart preservation by HEVP can be extended up to 8 hours, without compromising post-HTx recipient survival. HEVP may assist in overcoming limitations in preservation time associated with HTx, without increasing PGD risk.

Background: Ventilator-associated pneumonia is common and is treated using nebulized antibiotics. Although adequate pulmonary biodistribution is important for antibiotic effect, there is a lack of data for both intravenous (IV) and nebulized antibiotic administration during mechanical ventilation.Objective: To describe the comparative pulmonary regional distribution of IV and nebulized technetium (99m)-labeled tobramycin (Tc-99m-tobramycin) 400 mg in a mechanically-ventilated ovine model.Methods: The study was performed in a mechanically-ventilated ovine model. Tc-99m-tobramycin 400 mg was obtained using a radiolabeling process. Computed tomography (CT) was performed. Ten sheep were given Tc-99m-tobramycin 400 mg via either an IV (five sheep) or nebulized (five sheep) route. Planar images (dorsal, ventral, left lateral and right lateral) were obtained using a gamma camera. Blood samples were obtained every 15 min for 1 h (4 time points) and lung, liver, both kidney, and urine samples were obtained post-mortem.Results: Ten sheep were anesthetized and mechanically ventilated. Whole-lung deposition of nebulized Tc-99m-tobramycin 400 mg was significantly lower than with IV (8.8% vs. 57.1%, P < 0.001). For both administration routes, there was significantly lower deposition in upper lung zones compared with the rest of the lungs. Dorsal deposition was significantly higher with nebulized Tc-99m-tobramycin 400 mg compared with IV (68.9% vs. 58.9%, P = 0.003). Lung concentrations of Tc-99m-tobramycin were higher with IV compared with nebulized administration. There were significantly higher concentrations of Tc-99m-tobramycin in blood, liver and urine with IV administration compared with nebulized.Conclusions: Nebulization resulted in lower whole and regional lung deposition of Tc-99m-tobramycin compared with IV administration and appeared to be associated with low blood and extra-pulmonary organ concentrations. (C) 2020 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.

Purpose Brain death (BD) causes metabolic and energetic imbalances leading to cardiac dysfunction, and predisposes the donor heart to further injury following heart transplantation (HTx). The metabolic mechanisms required for myocardial energy production during BD and subsequent HTx are poorly understood. Our aim was to determine the myocardial metabolic profile and mitochondrial function following donor BD and HTx. Methods Donor BD in sheep was induced by inflation of a catheter placed through the skull (catheter placement, but no inflation for SHAM), followed by 24 hrs monitoring, and heart procurement (n=6/group, BD vs. SHAM). Additional donor hearts exposed to BD/SHAM were flushed with cold St Thomas cardioplegia, and stored via cold static storage (CSS) for ∼2 hrs. Following standard orthotopic HTx, recipients were weaned off bypass and monitored for ≤6 hrs prior to heart procurement (n=4/group, BD-Tx vs. Sh-Tx). Cardiac mitochondrial function was assessed using high resolution respirometry. Metabolic profiles were determined in hearts using metabolomics. Cardiac mitochondrial function was also determined in two sheep that underwent HTx following BD and 8 hr hypothermic ex vivo perfusion (HEVP) preservation. Results BD caused significant right ventricular (RV) mitochondrial uncoupling (vs. SHAM). HTx following CSS also impaired RV mitochondrial function, with these effects more pronounced in hearts exposed to both donor BD and HTx. Early findings show that HEVP improved cardiac mitochondrial function post-HTx (vs. CSS). Metabolically, BD increased myocardial amino-acid utilisation and accumulation of glucose metabolites. Post-HTx, particularly in those exposed to donor BD, there was a significant decrease in metabolites involved in mitochondrial respiration (eg. NAD, Acetyl-CoA) and accumulation of fatty acids and xanthine (purine breakdown). Conclusion BD appears to trigger cardiac mitochondrial uncoupling. This may be a protective mechanism against higher amino-acid utilisation and glucose accumulation, in order to maintain adequate mitochondrial function for cell survival. HTx following CSS, particularly from BD donors, induces significant mitochondrial dysfunction, which occurs in response to upstream metabolic impairments. Strategies that improve cardiac mitochondrial function or metabolism (eg. HEVP) may assist to improve HTx outcomes.

the intervention group (18.1%, 19/105 patients) and control group (30.4%, 31/102 patients) ( 2 =4.271, p=0.039). The intervention significantly lowered the number of PrI events developing over time (Logrank [Mantel–Cox] =11.842, p=0.001). Conclusions: The InSPiRE protocol resulted in significant reductions in thecumulative incidenceand time tooccurrenceofPrIs. The protocol was tailored to the ICU population and assisted registered nurses in delivering quality-focused patient care.

Patients requiring ECMO have acquired haemostatic disorders due to a vast interplay of factors including drugs, disease and device. In this heterogenous population it is impossible to define the isolated and combined effects of critical illness and ECMO on haemostasis. This study aimed to characterise changes in haemostasis attributable to ECMO in an in vivo ovine model using ROTEM® and Multiplate® analysis. In our validated model, 10 healthy sheep and 10 sheep with smoke-induced acute lung injury (S-ALI) were supported on venovenousECMO. Heparin infusioncommencedat4 U/kg/h to achieve activated clotting time of 200–300 s. Samples were collected at baseline, pre-ECMO and 0.25, 1, 1.5 and 2 h post-ECMO initiation. Analysis included platelet counts, EXTEM and FIBTEM on ROTEM®, and Multiplate® analysis with ADP and collagen agonists. For both groups, platelet count remained within normal range. ECMO induced no significant changes to ADP or collagen-induced platelet aggregation or EXTEM clotting time. EXTEM clot formation time (CFT) was increased (p less than 0.01) and EXTEM maximum clot firmness (MCF) (p less than 0.001) was decreased compared to baseline for both groups throughout ECMO. A smaller decrease in FIBTEM-MCF was documented during ECMO in healthy sheep (p less than 0.05) compared to sheep with S-ALI prior (p less than 0.01). ECMOinduces an increase in clot formation time and decrease in fibrinogen function and overall clot quality in healthy sheep. S-ALIprior to ECMO exacerbates these haemostatic alterations. Platelet number and function was maintained during ECMO, which, when assessed with the decrease in EXTEM-MCF and FIBTEM-MCF, suggests fibrinogen may be central to these haemostatic alterations.

Background: Echocardiography plays a fundamental role in cannulae insertion and positioning for venovenous extracorporeal membrane oxygenation (VV-ECMO). Correct access (AC) and return cannulae (RC) orientation is required to prevent recirculation. The aim of this study was to compare a novel imaging technique, intracatheter echocardiography (iCATHe), with conventional intracardiac echocardiography (ICE) to guide placement of both cannulae...

Background: The echocardiographically derived Tei index has been described as a non-invasive measure of overall myocardial performance. Data showing the relationshipbetweenTei indexand invasivelymeasuredfilling pressures is limited.We therefore sought to determine the correlation between invasively assessed left ventricular filling pressures and the Tei index in patients undergoing cardiac catheterisation for non ST-elevation acute coronary syndromes (NSTEACS). Methods: A total of 20 patients with NSTEACS underwent a limited transthoracic echocardiogram immediately prior to invasive left heart catheterisation to determine isovolumic contraction time (IVCT), isovolumic relexation time (IVRT) and ejection time (ET). Patients in atrial fibrillation (AF) were excluded. The Tei index was calculated as Tei = (IVCT+ IVRT)/ET. Invasivemeasurement of left ventricular filling pressure was then performed with a pigtail catheter inmid shallow expiration. Pre-Awave left ventricular diastolic pressure (pre-A LVDP) and left ventricular end diastolic pressure (LVEDP) were recorded. Results: The mean age of patients was 64.1 years, and 72% were males. All patients had Troponin+ve ACS. The mean LVEF was 52%. Angiographic findings included three vessel disease in 12.5% and LAD culprit lesions in 25%. A positive correlation was found between Tei Index and pre-A LVDP (Spearman’s rho 0.632; p= 0.005). A positive correlation was also found between Tei Index and LVEDP (Spearman’s rho 0.561; p= 0.015). Conclusions: The Tei index is a valid non-invasive surrogate of elevated filling pressures in patients with NSTEACS, and should be utilisedmore frequently in routine clinical practice.