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Background A lung transplant is the last resort treatment for many patients with advanced lung disease. The majority of donated lungs come from donors following brain death (BD). The endothelin axis is upregulated in the blood and lung of the donor after BD resulting in systemic inflammation, lung damage and poor lung graft outcomes in the recipient. Tezosentan (endothelin receptor blocker) improves the pulmonary haemodynamic profile; however, it induces adverse effects on other organs at high doses. Application of ex vivo lung perfusion (EVLP) allows the development of organ-specific hormone resuscitation, to maximise and optimise the donor pool. Therefore, we investigate whether the combination of EVLP and tezosentan administration could improve the quality of donor lungs in a clinically relevant 6-h ovine model of brain stem death (BSD). Methods After 6 h of BSD, lungs obtained from 12 sheep were divided into two groups, control and tezosentan-treated group, and cannulated for EVLP. The lungs were monitored for 6 h and lung perfusate and tissue samples were processed and analysed. Blood gas variables were measured in perfusate samples as well as total proteins and pro-inflammatory biomarkers, IL-6 and IL-8. Lung tissues were collected at the end of EVLP experiments for histology analysis and wet-dry weight ratio (a measure of oedema). Results Our results showed a significant improvement in gas exchange [elevated partial pressure of oxygen (P = 0.02) and reduced partial pressure of carbon dioxide (P = 0.03)] in tezosentan-treated lungs compared to controls. However, the lungs hematoxylin–eosin staining histology results showed minimum lung injuries and there was no difference between both control and tezosentan-treated lungs. Similarly, IL-6 and IL-8 levels in lung perfusate showed no difference between control and tezosentan-treated lungs throughout the EVLP. Histological and tissue analysis showed a non-significant reduction in wet/dry weight ratio in tezosentan-treated lung tissues (P = 0.09) when compared to control. Conclusions These data indicate that administration of tezosentan could improve pulmonary gas exchange during EVLP.

Background Nebulised antibiotics are frequently used for the prevention or treatment of ventilator-associated pneumonia. Many factors may influence pulmonary drug concentrations with inaccurate dosing schedules potentially leading to therapeutic failure and/or the emergence of antibiotic resistance. We describe a research pathway for studying the pharmacokinetics of a nebulised antibiotic during mechanical ventilation using in vitro methods and ovine models, using tobramycin as the study antibiotic. Methods In vitro studies using a laser diffractometer and a bacterial-viral filter were used to measure the effect of the type and size of tracheal tubes and antibiotic concentration on the particle size distribution of the tobramycin 400 mg (4 ml; 100 mg/ml) and 160 mg (4 ml, 40 mg/ml) aerosol and nebulised mass delivered. To compare the regional drug distribution in the lung of two routes (intravenous and nebulised) of drug administration of tobramycin 400 mg, technetium-99m-labelled tobramycin 400 mg with planar nuclear medicine imaging was used in a mechanically ventilated ovine model. To measure tobramycin concentrations by intravenous and nebulised tobramycin 400 mg (4 ml, 100 mg/ml) administration in the lung interstitial space (ISF) fluid and blood of mechanically ventilated sheep, the microdialysis technique was used over an 8-h duration. Results Tobramycin 100 mg/ml achieved a higher lung dose (121.3 mg) compared to 40 mg/ml (41.3 mg) solution. The imaging study with labelled tobramycin indicated that nebulised tobramycin distributed more extensively into each lung zone of the mechanically ventilated sheep than intravenous administration. A higher lung ISF peak concentration of tobramycin was observed with nebulised tobramycin (40.8 mg/l) compared to intravenous route (19.0 mg/l). Conclusions The research methods appear promising to describe lung pharmacokinetics for formulations intended for nebulisation during mechanical ventilation. These methods need further validation in an experimental pneumonia model to be able to contribute toward optimising dosing regimens to inform clinical trials and/or clinical use.

Background Echocardiography is a key investigation in the management of patients on extracorporeal membrane oxygenation (ECMO). However, echocardiographic images are often non-diagnostic in this patient population. Contrast-enhanced echocardiography may overcome many of these limitations but contrast microspheres are hydrodynamically labile structures prone to destruction from shear forces and turbulent flow, which may exist within an ECMO circuit. This study sought to evaluate microsphere destruction (utilising signal intensity as a marker of contrast concentration) during transit through an ECMO circuit. Methods Activated Definity® contrast was diluted to 50 ml with normal saline and infused into a crystalloid primed ex vivo ECMO with a Quadrox oxygenator at 150 ml/h. Imaging was performed on pre- and post-pump head/oxygenator sections of the circuit using a Philips iE33 scanner and S5-1 transducer. Five-millimetre regions of interest were placed in the centre of the ultrasound field. Average signal intensity (decibels) was calculated at speeds of 1000, 2000, 3000 and 4000 rpm and then repeated with an infusion rate of 300 ml/h. The oxygenator was then spliced out of the circuit and the measures repeated. Results There was a significant reduction in contrast concentration during passage through the ECMO circuit at all speeds (with higher pump head speeds resulting in greater microsphere destruction). In a circuit with an oxygenator, relative decrease in signal intensity was 21.4 versus 5.2 % without an oxygenator. There was significant destruction of contrast microspheres during passage through the ECMO circuit at all pump head speeds. An oxygenator contributed to microsphere destruction at a significantly greater level than the pump head alone. There was no significant difference in mean signal intensity reduction in the circuit between an infusion of 150 or 300 ml/h (3.5 ± 3.2 versus 3.6 ± 2.5 dB, respectively, p = 0.79). Conclusions Flow of contrast through an ECMO circuit results in significant destruction of microspheres. Circuits with an oxygenator result in significantly greater levels of contrast destruction than by the pump head alone. Clinicians should be cognisant of the relationship between ECMO circuit configurations, pump head speed and contrast destruction when performing a contrast-enhanced echocardiogram in patients supported with ECMO. Electronic supplementary material The online version of this article (doi:10.1186/s40635-016-0079-0) contains supplementary material, which is available to authorized users.

Introduction Ex vivo experiments in extracorporeal membrane oxygenation (ECMO) circuits have identified octanol-water partition coefficient (logP, a marker of lipophilicity) and protein binding (PB) as key drug factors affecting pharmacokinetics (PK) during ECMO. Using ovine models, in this study we investigated whether these drug properties can be used to predict PK alterations of antimicrobial drugs during ECMO. Methods Single-dose PK sampling was performed in healthy sheep (HS, n = 7), healthy sheep on ECMO (E24H, n = 7) and sheep with smoke inhalation acute lung injury on ECMO (SE24H, n = 6). The sheep received eight study antimicrobials (ceftriaxone, gentamicin, meropenem, vancomycin, doripenem, ciprofloxacin, fluconazole, caspofungin) that exhibit varying degrees of logP and PB. Plasma drug concentrations were determined using validated chromatographic techniques. PK data obtained from a non-compartmental analysis were used in a linear regression model to predict PK parameters based on logP and PB. Results We found statistically significant differences in pH, haemodynamics, fluid balance and plasma proteins between the E24H and SE24H groups (p ss) in both the E24H and SE24H groups (p p = 0.9) and no relationship with clearance (CL) in all study groups. Although we observed an increase in CL for highly PB drugs in ECMO sheep, PB exhibited a weaker negative linear relationship with both CL (HS, p = 0.01; E24H, p p ss (HS, p = 0.01; E24H, p = 0.004; SE24H, p =0.05) in the final model. Conclusions Lipophilic antimicrobials are likely to have an increased Vss and decreased CL during ECMO. Protein-bound antimicrobial agents are likely to have reductions both in CL and Vss during ECMO. The strong relationship between lipophilicity and Vss seen in both the E24H and SE24H groups indicates circuit sequestration of lipophilic drugs. These findings highlight the importance of drug factors in predicting antimicrobial drug PK during ECMO and should be a consideration when performing and interpreting population PK studies.

Background Echocardiography plays a fundamental role in cannulae insertion and positioning for extracorporeal membrane oxygenation (ECMO). Optimal access and return cannulae 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 ECMO access and return venous cannulae. Methods Twenty sheep were commenced on veno-venous ECMO (VV ECMO). Access and return ECMO cannulae were positioned using an ICE-guided technique. Following the assessment of cannulae position, the ICE probe was then introduced inside the cannulae, noting location of the tip. After 24 h, the sheep were euthanized and cannulae position was determined at post mortem. The two-tailed McNemar test was used to compare iCATHe with ICE cannulae positioning. Results ICE and iCATHe imaging was possible in all 20 sheep commenced on ECMO. There was no significant difference between the two methods in assessing access cannula position (proportion correct for each 90%, incorrect 10%). However, there was a significant difference between ICE and iCATHe success rates for the return cannula (p = 0.001). Proportion correct for iCATHe and ICE was 80% and 15% respectively. iCATHe was 65% more successful (95% CI 27% to 75%) at predicting the placement of the return cannula. There were no complications related to the ICE or iCATHe imaging. Conclusion iCATHe is a safe and feasible imaging technique to guide real-time VV ECMO cannulae placement and improves accuracy of return cannula positioning compared to ICE. Electronic supplementary material The online version of this article (doi:10.1186/2197-425X-2-2) contains supplementary material, which is available to authorized users.