Rebecca Cusack

Clinical review: Exogenous surfactant therapy for acute lung injury/acute respiratory distress syndrome--where do we go from here?

Acute lung injury and acute respiratory distress syndrome (ARDS) are characterised by severe hypoxemic respiratory failure and poor lung compliance. Despite advances in clinical management, morbidity and mortality remains high. Supportive measures including protective lung ventilation confer a survival advantage in patients with ARDS, but management is otherwise limited by the lack of effective pharmacological therapies. Surfactant dysfunction with quantitative and qualitative abnormalities of both phospholipids and proteins are characteristic of patients with ARDS. Exogenous surfactant replacement in animal models of ARDS and neonatal respiratory distress syndrome shows consistent improvements in gas exchange and survival. However, whilst some adult studies have shown improved oxygenation, no survival benefit has been demonstrated to date. This lack of clinical efficacy may be related to disease heterogeneity (where treatment responders may be obscured by nonresponders), limited understanding of surfactant biology in patients or an absence of therapeutic effect in this population. Crucially, the mechanism of lung injury in neonates is different from that in ARDS: surfactant inhibition by plasma constituents is a typical feature of ARDS, whereas the primary pathology in neonates is the deficiency of surfactant material due to reduced synthesis. Absence of phenotypic characterisation of patients, the lack of an ideal natural surfactant material with adequate surfactant proteins, coupled with uncertainty about optimal timing, dosing and delivery method are some of the limitations of published surfactant replacement clinical trials. Recent advances in stable isotope labelling of surfactant phospholipids coupled with analytical methods using electrospray ionisation mass spectrometry enable highly specific molecular assessment of phospholipid subclasses and synthetic rates that can be utilised for phenotypic characterisation and individualisation of exogenous surfactant replacement therapy. Exploring the clinical benefit of such an approach should be a priority for future ARDS research.

A repeated measures, randomised cross-over trial, comparing the acute exercise response between passive and active sitting in critically ill patients

BackgroundEarly mobilisation of critically ill patients is safe and beneficial, but the metabolic cost of exercise remains unquantified. This study compared the acute exercise response in critically ill participants during passive and active sitting.MethodWe conducted a prospective, randomised, cross-over study, in ventilated patients receiving rehabilitative physiotherapy. Ten participants completed a passive chair transfer, or a sit on the edge of the bed, followed by the alternate exercise activity on the consecutive day. The primary outcome measure was oxygen consumption.ResultsIn comparison to resting supine, a passive chair transfer elicited no change in oxygen consumption, carbon dioxide production or minute ventilation; but mean arterial pressure (91.86 mmHg (95% CI 84.61 to 99.10) to 101.23 mmHg (95% CI 93.35 to 109.11) (p = 0.002)) and heart rate (89.13 bpm (95% CI 77.14 to 101.13) to 97.21 bpm (95% CI 81.22 to 113.20) (p = 0.008)) increased. Sitting on the edge of the bed resulted in significant increases in oxygen consumption (262.33 ml/min (95% CI 201.97 to 322.70) to 353.02 ml/min (95% CI 303.50 to 402.55), p = 0.002), carbon dioxide production (171.93 ml/min (95% CI 131.87 to 211.98) to 206.23 ml/min (95% CI 151.03 to 261.43), p = 0.026), minute ventilation (9.97 l/min (95% CI 7.30 to 12.65) to 12.82 l/min (95% CI 10.29 to 15.36), p < 0.001), mean arterial pressure (86.81 mmHg (95% CI 77.48 to 96.14) to 95.59 mmHg (95% CI 88.62 to 102.56), p = 0.034) and heart rate (87.60 bpm (95% CI 73.64 to 101.56) to 94.91 bpm (95% CI 79.57 to 110.25), p = 0.007). When comparing the 2 activities, sitting on the edge of the bed elicited a significantly larger increase in oxygen consumption (90.69 ml/min (95% CI 44.04 to 137.34) vs 14.43 ml/min (95% CI -27.28 to 56.14), p = 0.007) and minute ventilation (2.85 l/min (95% CI 1.70 to 3.99) vs 0.74 l/min (95% CI -0.92 to 1.56), p = 0.012).ConclusionSitting on the edge of the bed is a more metabolically demanding activity than a passive chair transfer in critically ill patients.

Altered molecular specificity of surfactant phosphatidycholine synthesis in patients with acute respiratory distress syndrome

BackgroundAcute respiratory distress syndrome (ARDS) is a life-threatening critical illness, characterised by qualitative and quantitative surfactant compositional changes associated with premature airway collapse, gas-exchange abnormalities and acute hypoxic respiratory failure. The underlying mechanisms for this dysregulation in surfactant metabolisms are not fully explored. Lack of therapeutic benefits from clinical trials, highlight the importance of detailed in-vivo analysis and characterisation of ARDS patients according to patterns of surfactant synthesis and metabolism.MethodsTen patients with moderate to severe ARDS were recruited. Most (90%) suffered from pneumonia. They had an infusion of methyl-D9-choline chloride and small volume bronchoalveolar lavage fluid (BALF) was obtained at 0,6,12,24,48,72 and 96 hours. Controls were healthy volunteers, who had BALF at 24 and 48 hours after methyl-D9-choline infusion. Compositional analysis and enrichment patterns of stable isotope labelling of surfactant phosphatidylcholine (PC) was determined by electrospray ionisation mass spectrometry.ResultsBALF of patients with ARDS consisted of diminished total PC and fractional PC16:0/16:0 concentrations compared to healthy controls. Compositional analysis revealed, reductions in fractional compositions of saturated PC species with elevated levels of longer acyl chain unsaturated PC species. Molecular specificity of newly synthesised PC fraction showed time course variation, with lower PC16:0/16:0 composition at earlier time points, but achieved near equilibrium with endogenous composition at 48 hours after methyl-D9-choline infusion. The enrichment of methyl-D9-choline into surfactant total PC is nearly doubled in patients, with considerable variation between individuals.ConclusionsThis study demonstrate significant alterations in composition and kinetics of surfactant PC extracted from ARDS patients. This novel approach may facilitate biochemical phenotyping of ARDS patients according to surfactant synthesis and metabolism, enabling individualised treatment approaches for the management of ARDS patients in the future.

Parallels between astronauts and terrestrial patients – taking physiotherapy rehabilitation “To infinity and beyond”

Exposure to the microgravity environment induces physiological changes in the cardiovascular, musculoskeletal and sensorimotor systems in healthy astronauts. As space agencies prepare for extended duration missions, it is difficult to predict the extent of the effects that prolonged exposure to microgravity will have on astronauts. Prolonged bed rest is a model used by space agencies to simulate the effects of spaceflight on the human body, and bed rest studies have provided some insights into the effects of immobilisation and inactivity. Whilst microgravity exposure is confined to a relatively small population, on return to Earth, the physiological changes seen in astronauts parallel many changes routinely seen by physiotherapists on Earth in people with low back pain (LBP), muscle wasting diseases, exposure to prolonged bed rest, elite athletes and critically ill patients in intensive care. The medical operations team at the European Space Agency are currently involved in preparing astronauts for spaceflight, advising on exercises whilst astronauts are on the International Space Station, and reconditioning astronauts following their return. There are a number of parallels between this role and contemporary roles performed by physiotherapists working with elite athletes and muscle wasting conditions. This clinical commentary will draw parallels between changes which occur to the neuromuscular system in the absence of gravity and conditions which occur on Earth. Implications for physiotherapy management of astronauts and terrestrial patients will be discussed.

S18 Bronchoalveolar Lavage, Tracheal Wash and Induced Sputum Surfactant Phospholipid Kinetics from Healthy Volunteers

Introduction and Aims Pulmonary surfactant is a complex mixture of lipoproteins synthesised and secreted by alveolar type II cells. The assessment of surfactant synthetic function and metabolism may provide essential information in disease states characterised by surfactant dysfunction. Airway surfactant is thought to be of alveolar origin. However, surfactant kinetics from airway secretions may vary from alveolar surfactant. Stable isotope labelling of surfactant precursors enables dynamic mapping of surfactant PC molecular species. This study aimed to compare three surfactant recovery methods [bronchoalveolar lavage (BAL), tracheal wash (TW) and induced sputum (IS)] to assess surfactant PC kinetics in healthy adults. Surfactant phosphatidylcholine (PC) is synthesised de novo from choline via CDP-choline pathway. By labelling choline with deuterium, a naturally occurring isotope of hydrogen, it is possible to assess surfactant PC synthesis and metabolism in humans. Methods Healthy human volunteers had an infusion of methyl-D9-choline-chloride [3.6mg/kg] for 3 hours. BAL and TW specimens were taken at 24 and 48 hours and induced sputum samples were taken at 0, 8, 24, 48 and 96 hours after choline infusion. The lipid fraction was extracted with chloroform and methanol. The samples were analysed by triple quadrupole electro spray ionisation mass spectrometer (ESI/MS). The results are expressed in mean (+/–standard error of mean). Results Ten healthy volunteers were recruited. The endogenous PC composition from BAL and TW were similar. The newly synthesised PC fraction mirrored the endogenous composition at 48 hours for both BAL and TW IS PC composition and D9 labelled PC fraction was variable. The total PC D9-incorporation at 48 hours was higher than 24 hours for BAL (0.55±0.04%), TW (0.56±0.04%) and IS (0.58±0.06). PC16:0/16:0 D9-incorporation had significant correlation for BAL and TW (r2=0.8201, P<0.05). Conclusions Isotope labelling of choline using ESI/MS analytical method, it is possible to assess surfactant PC metabolism. The tracheal aspirate is an alternative technique to assess surfactant metabolism in patients otherwise unable to tolerate invasive bronchoscopy. This methodology may be utilised to assess surfactant synthetic function in patients with acute lung injury.

Abnormal liver phosphatidylcholine synthesis revealed in patients with acute respiratory distress syndrome

Acute respiratory distress syndrome (ARDS) is associated with a severe pro-inflammatory response; although decreased plasma cholesterol concentration has been linked to systemic inflammation, any association of phospholipid metabolic pathways with ARDS has not been characterized. Plasma phosphatidylcholine (PC), the major phospholipid of circulating lipoproteins, is synthesized in human liver by two biologically diverse pathways: the cytidine diphosphocholine (CDP):choline and phosphatidylethanolamine N-methyltransferase (PEMT) pathways. Here, we used ESI-MS/MS both to characterize plasma PC compositions and to quantify metabolic fluxes of both pathways using stable isotopes in patients with severe ARDS and in healthy controls. Direct incorporation of methyl-D9-choline estimated CDP:choline pathway flux, while PEMT flux was determined from incorporations of one and two methyl-D3 groups derived from methyl-D9-choline. The results of MS/MS analysis showed significant alterations in plasma PC composition in patients with ARDS versus healthy controls. In particular, the increased overall methyl-D9-PC enrichment and, most importantly, the much lower methyl-D3-PC and methyl-D6-PC enrichments suggest increased flux through the CDP:choline pathway and reduced flux through the PEMT pathway in ARDS. To our knowledge, this study is the first to demonstrate significant plasma PC molecular compositional changes combined with associated alterations in the dynamics of PC synthetic pathways in patients with ARDS.

Quality improvement: The delivery of true early mobilisation in an intensive care unit

Early mobilisation initiatives within the critical care environment have been shown to improve outcomes for patients. Early mobilisation has been defined as occurring within the first two to five days of the intensive care stay, but in practice this can be difficult to deliver. We conducted a quality improvement (QI) project to deliver early mobilisation in a large general intensive care unit. Mechanically ventilated medical patients received an integrated package of care involving two additional daily sessions of mobility therapy, in combination with minimal sedation where possible. Prospective baseline data was collected from January to March 2012; the QI project commenced in April 2012. Improvement cycle 1 completed in March 2015 and improvement cycle 2 in March 2016. Results have suggested a reduction in time to first mobilisation for intensive care survivors from 16.3 days in 2012, to 4.3 days at the end of improvement cycle 2. This was associated with a decrease in mean intensive care length of stay from 20.8 days in 2012, to 11.2 days at the end of improvement cycle 2. This QI project enabled patients to mobilise out of bed within the first five days of their intensive care stay and to be discharged earlier from the ICU, on going analysis is required to verify these findings.

Physical rehabilitation interventions for adult patients with critical illness across the continuum of recovery

Background: Patients admitted to the intensive care unit with critical illness often experience significant physical impairments, which typically persist for many years following resolution of the original illness. Physical rehabilitation interventions that enhance restoration of physical function have been evaluated across the continuum of recovery following critical illness including within the intensive care unit, following discharge to the ward and beyond hospital discharge. Multiple systematic reviews have been published appraising the expanding evidence investigating these physical rehabilitation interventions, although there appears to be variability in review methodology and quality. We aim to conduct an overview of existing systematic reviews of physical rehabilitation interventions for adult intensive care patients across the continuum of recovery. Methods/design: This protocol has been developed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocol (PRISMA-P) guidelines. We will search the Cochrane Systematic Review Database, Database of Abstracts of Reviews of Effectiveness, Cochrane Central Register of Controlled Trials, MEDLINE, Excerpta Medica Database and Cumulative Index to Nursing and Allied Health Literature databases. We will include systematic reviews of randomised controlled trials of adult patients, admitted to the intensive care unit and who have received physical rehabilitation interventions at any time point during their recovery. Data extraction will include systematic review aims and rationale, study types, populations, interventions, comparators, outcomes and quality appraisal method. Primary outcomes of interest will focus on findings reflecting recovery of physical function. Quality of reporting and methodological quality will be appraised using the PRISMA checklist and the Assessment of Multiple Systematic Reviews tool. Discussion: We anticipate the findings from this novel overview of systematic reviews will contribute to the synthesis and interpretation of existing evidence regarding physical rehabilitation interventions and physical recovery in post-critical illness patients across the continuum of recovery. Systematic review registration: PROSPERO CRD42015001068.BackgroundPatients admitted to the intensive care unit with critical illness often experience significant physical impairments, which typically persist for many years following resolution of the original illness. Physical rehabilitation interventions that enhance restoration of physical function have been evaluated across the continuum of recovery following critical illness including within the intensive care unit, following discharge to the ward and beyond hospital discharge. Multiple systematic reviews have been published appraising the expanding evidence investigating these physical rehabilitation interventions, although there appears to be variability in review methodology and quality. We aim to conduct an overview of existing systematic reviews of physical rehabilitation interventions for adult intensive care patients across the continuum of recovery.Methods/designThis protocol has been developed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocol (PRISMA-P) guidelines. We will search the Cochrane Systematic Review Database, Database of Abstracts of Reviews of Effectiveness, Cochrane Central Register of Controlled Trials, MEDLINE, Excerpta Medica Database and Cumulative Index to Nursing and Allied Health Literature databases. We will include systematic reviews of randomised controlled trials of adult patients, admitted to the intensive care unit and who have received physical rehabilitation interventions at any time point during their recovery. Data extraction will include systematic review aims and rationale, study types, populations, interventions, comparators, outcomes and quality appraisal method. Primary outcomes of interest will focus on findings reflecting recovery of physical function. Quality of reporting and methodological quality will be appraised using the PRISMA checklist and the Assessment of Multiple Systematic Reviews tool.DiscussionWe anticipate the findings from this novel overview of systematic reviews will contribute to the synthesis and interpretation of existing evidence regarding physical rehabilitation interventions and physical recovery in post-critical illness patients across the continuum of recovery.Systematic review registrationPROSPERO CRD42015001068.