Background: Lung volume reduction surgery is a proven treatment for emphysematous patients with hyperinflation, but the precarious health of candidates has prompted development of less invasive approaches. Bronchoscopic implanted endobronchial coils, shape-memory nitinol filaments, shrink emphysematous lung tissue to restore elastic recoil and to tether airways to maintain patency. Studies have demonstrated an acceptable safety profile and improvements in lung function, exercise capacity, and quality of life out to 3 years. Volume reduction is key. However, data for longer-term survival are limited. Objective: The aim of this study was to establish the 5-year overall and transplant-free survivals of subjects whose procedure in the first randomized controlled trial, RESET, achieved clinically meaningful reduction in residual volume (RV). Methods: Patients and their primary care doctors were contacted to confirm vital status and history of additional interventions. Death certificates were acquired via the General Registry Office. Survival time was calculated for responders achieving a reduction of ≥10% in RV compared to non-responders. Results: 39 patients completed the planned bilateral sequential treatments. Six patients received unilateral implants. At 5 years, 22 patients had died. The overall survivals at 1, 2, 3, 4 and 5 years were 88.9, 88.9, 77.8, 64.4 and 50.6%, respectively. Two patients underwent lung transplantation at 52 and 59 months and were alive at 5 years. The transplant-free (TF) survivals at 1, 2, 3, 4 and 5 years were 88.9, 88.9, 77.8, 64.4 and 46.7%, respectively. Volume reduction responders (n = 18) at 3 months had a 5-year TF survival of 66.7% compared to 36.4% for non-responders (n = 22; p = 0.07). Higher baseline inspiratory capacity (HR 0.13, 95% CI 0.02–0.73; p = 0.02) and partial pressure of oxygen (pO2) (HR 0.57, 95% CI 0.38–0.86; p < 0.01) values were predictive of survival for the entire cohort and were not influenced by age. Conclusions: Endobronchial coil implantation appears to confer a 5-year survival advantage for those who achieved a 10% reduction in RV at 3 months. Ongoing trials are designed to clarify the mechanisms of action of coils and to refine patient selection.

BACKGROUND:There is a clinical need for therapeutic options to reduce hyperinflation associated with severe emphysema. Endobronchial Coils (coils) are nitinol devices implanted bronchoscopically under fluoroscopic guidance to re-tension the lung. We report the medium term effectiveness and safety of coils in a study of patients with emphysema.METHODS:Forty five subjects with severe airflow obstruction and hyperinflation received bilateral sequential treatment with coils (30 day interval between treatments) as part of a randomised controlled trial with a primary endpoint 90 days after the final treatment (Clinicaltrials.gov NCT01334307). Further assessments were made at 180 and 360 days and in this study the primary outcome was the effect of coil treatment on the St. George's Respiratory Questionnaire (SGRQ) 360 days following treatment.RESULTS:At 360 days following treatment, there was an improvement in the SGRQ score of -6.1±14.0 points (p = 0.01) compared to baseline. Improvements in secondary outcomes were seen with increases in forced expiratory volume in the first second of 8.9 ±22.2% (p = 0.002) and 6-minute walking distance of 34.1±52.4m (p = 0.003). The safety profile was acceptable out to 360 days post-treatment.CONCLUSIONS:Statistically and clinically meaningful benefits in quality of life, exercise capacity and pulmonary function in patients treated with coils are sustained twelve months after treatment.TRIAL REGISTRATION INFORMATION:Clinicaltrials.gov NCT01334307.

Background The predominant pathophysiology in severe emphysema with gas trapping and hyperinflation is that of dynamic airway collapse on minimal expiratory effort. This limits the benefit from drug therapy. Safer and cheaper alternatives to lung volume reduction surgery (LVRS), which has success in selected patients with low exercise capacity and upper lobe-predominant emphysema, are being developed. Endobronchial valve treatment has been shown to be beneficial to patients with heterogenous disease in the absence of collateral ventilation. RePneu Lung Volume Reduction Coils (LVRCs) are self-actuating implantable devices composed of nitinol. They are implanted bronchoscopically using conscious sedation. The LVRC is delivered into targeted airways using fluoroscopic guidance, and when its sheath is removed recoils to it original pre-determined shape. Methods In a prospective randomised study of LVRCs on patients with severe emphysema and hyperinflation, 63 patients were screened at 3 centres in the United Kingdom with 23 randomised to treatment with LVRCs and 24 to best medical care (control). LVRC patients were initially treated in one lung, with the contralateral lung treated after one month if appropriate. The primary end point was the difference between treatment and control groups in the St. George’s Respiratory Questionnaire (SGRQ) 90 days post-final treatment. The trial is registered with ClinicalTrials.gov (NCT01334307). Results Significant improvements in the treatment group compared to control group were observed for the primary end point mean SGRQ (Δ-10.54 points, p=0.004), as well as secondary end points mean six-minute walk distance (Δ+70.39 metres, p<0.001) and forced expiratory volume in one second (Δ+12.81%, p=0.009). Between group difference in change in mean residual volume did not reach significance (Δ-0.35 litres, p=0.051), despite a 0.64 litre reduction in the treatment group. There was a good safety profile with treatment. Conclusions Treatment with endobronchial coils in patients with severe emphysema and hyperinflation significantly improves quality of life, exercise capacity and pulmonary function with a good safety profile. LVRCs present a novel, safe, and minimally invasive treatment option for patients with both homogenous and heterogenous emphysema, with benefits unaffected by collateral ventilation. A larger randomised controlled pivotal trial with longer follow-up is now needed. Funding shared by PneumRx and study sites.

Background Few treatment options exist for patients with severe emphysema. We assessed the clinical benefits and safety of lung volume reduction coils (LVRCs) for the treatment of patients with severe emphysema with hyperinflation.Methods In a randomised study, we recruited patients with severe emphysema (aged >= 35 years) from three centres in the UK. Using a computer-generated randomisation sequence, we randomly allocated patients in a one-to-one ratio (block sizes of four and stratified by centre) to either LVRC treatment (treatment group) or best medical care (usual care group). The primary endpoint was the difference in response in the St George's Respiratory Questionnaire (SGRQ) between treatment and usual care groups at 90 days after final treatment (by intention-to-treat analysis). The trial is registered with ClinicalTrials.gov, number NCT01334307.Findings Between Jan 27, 2010, to Oct 25, 2011, we recruited and randomly allocated 47 patients: 23 to treatment and 24 to usual care (23 patients in each group were included in the intention-to-treat analysis). SGRQ response at 90 days after final treatment was greater in the treatment group than it was in the usual care group (between-group difference in change from baseline -8.36 points [95% CI -16.24 to -0.47]; p=0.04). We detected no between-group difference in serious adverse events.Interpretation Our findings suggest that treatment with endobronchial coils can improve quality of life for patients with severe emphysema and hyperinflation.

Introduction: Fosfomycin and tobramycin in a 4:1 (w/w) ratio (F:T) has been developed for treatment of bacterial respiratory infections.The aim of this study was to investigate whether this combination was synergistic against respiratory pathogens under aerobic and anaerobic conditions.Methods: Clinical P. aeruginosa (PA, n = 15) isolates were grouped according to their F:T MIC: i. 10 mg/L; ii.>10-20 mg/L and iii.>20 mg/L.Five PA isolates from each group and a further 5 MRSA isolates were selected for time-kill studies using F:T at a concentration of 2x aerobic MIC and both antibiotics alone at the concentration used in the combination.Synergy was defined as a 2 log 10 reduction in viable count at 24 h with the combination compared to the most active agent alone. Results:The F:T combination was found to be synergistic against 20% and 45% of isolates under aerobic and anaerobic conditions, respectively (Table ).Some PA isolates had re-grown at 24 h when tested against fosfomycin and tobramycin alone under both conditions; however, F:T remained bactericidal at 24 h.F:T showed no antagonism when tested against any of the isolates under either growth condition. Conclusion:This study demonstrates by time-kill that F:T is synergistic against clinical PA and MRSA isolates with synergistic activity more pronounced under anaerobic conditions.F:T may therefore be a viable treatment option for anaerobic and aerobic infections caused by these bacterial respiratory pathogens.

Pancreatic endocrine dysfunction in patients with cystic fibrosis heralds declining pulmonary function and a six-fold rise in mortality. Insulin therapy increases weight and reduces decline in lung function. Optimal timing of initiation remains contentious but early intervention may maximise benefit. We explored the optimal timing of initiation of therapy and characterised the frequency and usual symptoms of hypoglycaemia.Fifty-four patients with cystic fibrosis treated with insulin were compared up to five years pre and post insulin initiation with respect to weight gain and lung function. Frequency and usual symptoms of hypoglycaemia were assessed using the Hypoglycemia Symptoms Awareness Questionnaire.Mean age was 27.6(16-52) years. In the five years preceding insulin therapy, FEV1 declined from 2.6 +/- 0.14L to 1.78 +/- 0.12L (p<0.001). In the group as a whole, rate of decline was arrested with insulin initiation; the mean five-year post insulin FEV1 was 1.74 +/- 0.20L (p=0.15). When stratified according to oral glucose tolerance testing at initiation the rate of decline was significant in patients with impaired glucose tolerance (p=0.02) but not normal glucose tolerance nor overt cystic fibrosis diabetes mellitus. Insulin therapy increased weight from 53.08 +/- 1.53kg to 56.22 +/- 2.08kg (p=0.05). Hypoglycaemia was common and 75% of respondents scored results indicative of hypoglycaemia unawareness.This study confirms that the favourable effect of insulin upon lung function in patients with cystic fibrosis correlates with the degree of glucose intolerance at baseline. Hypoglycaemia is an important clinical issue. Copyright (C) 2011 John Wiley & Sons.

Background: Reduced diaphragm contractility occurs in some healthy subjects when they exercise to exhaustion. This indicates low frequency fatigue, which may contribute to task failure. We hypothesised that patients with congestive heart failure (CHF) might be especially vulnerable to the development of low frequency diaphragm fatigue after exhaustive exercise.Aims: To study the effect of exhaustive incremental cycle exercise on diaphragm contractility in patients with CHF.Methods: 12 patients with CHF with an ejection fraction of 36.5 +/- 7.3% and 12 healthy age-matched control subjects performed an incremental cycle test to exhaustion. The unpotentiated twitch transdiaphragmatic pressure (twitch Pdi) in response to bilateral anterolateral magnetic phrenic nerve stimulation (BAMPS) was measured before and after exercise.Results: Twitch Pdi at baseline was 20.2 +/- 6.7 cmH(2)O in the CHF group and 20.3 +/-.3 cmH(2)O in the controls (p=0.957). 25 and 35 min post exercise the values were 19.9 +/- 5.4 and 20.0 +/- 5.1 cmH(2)O in the CHF group and 20.6 +/- 4.3 and 21.2 +/- 3.4 cmH(2)O in the control group; neither change was significant (F(2,27)=0.007, p=0.993; F(2,33)=0.144, p=0.866, respectively).Conclusion: When patients with CHF cycle to exhaustion, low frequency fatigue of the diaphragm does not occur, and this is unlikely to be an important factor limiting exercise capacity of such patients. (c) 2005 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.

Whole body exercise is followed by a depression of the diaphragm motor evoked potential (MEP). It is unknown whether the change is due to diaphragm activity or whole body exercise. To test the hypothesis that exercise-induced MEP depression was related to diaphragm activity, we performed two experiments. The first examined the effect of whole body exercise, performed with and without the use of non-invasive ventilation (NIV). NIV resulted in significant unloading of the diaphragm (pressure time product 101+/-68 cm H(2)O/s/min versus 278+/-95 cm H(2)O/s/min, p<0.001). Both conditions produced significant MEP depression compared to the control condition (% drop at 5 min, after exercise and exercise with NIV: 29 and 34%, p=0.77). Study 2 compared exercise with isocapnic hyperventilation. At 20 min the MEP had fallen by 29% in the exercise session versus 5% with hyperventilation (p=0.098). We conclude that the work of breathing during whole body exercise is not the primary driver of exercise-induced diaphragm MEP depression.

The costal and crural parts of the diaphragm differ in their embryological development and physiological function. It is not known if this is reflected in differences in their motor cortical representation. We compared the response of the costal and crural diaphragms using varying intensities of transcranial magnetic stimulation of the motor cortex at rest and during submaximal and maximal inspiratory efforts. The costal and crural motor evoked potential recruitment curves during submaximal inspiratory efforts were similar. The response to stimulation before, during and at 10 and 30 min after 44 consecutive maximal inspiratory efforts was also the same. Using paired stimulations to investigate intra-cortical facilitatory and inhibitory circuits we found no difference between the costal and crural response with varying interstimulus intervals, or when conditioning and test stimulus intensity were varied. We conclude that supraspinal control of the costal and crural diaphragm is identical during inspiratory tasks.

The effect of mechanical ventilation on the diaphragm motor cortex remains unknown. We assessed the effect of mechanical ventilation on diaphragm motor cortex excitability by measuring the costal and crural diaphragm motor-evoked potential (MEP) elicited by single and paired transcranial magnetic stimulation. In six healthy subjects, MEP recruitment curves of the costal and crural diaphragms were assessed at relaxed end expiration during spontaneous breathing [baseline tidal volume (Vt(baseline))] and isocapnic volume cycled ventilation delivered noninvasively (NIV) at three different levels of tidal volume (Vt(baseline), Vt(baseline) + 5 ml/kg liters, and Vt(baseline) + 10 ml/kg liters). The costal and crural diaphragm response to peripheral stimulation of the right phrenic nerve was not reduced by NIV. NIV reduced the costal and crural MEP amplitude during NIV (P < 0.0001) with the maximal reduction at Vt(baseline) + 5 ml/kg. Response to paired TMS showed that NIV (Vt(baseline) + 5 ml/kg) significantly increased the sensitivity of the cortical motoneurons to facilitatory (>9 ms) interstimulus intervals (P = 0.002), suggesting that the diaphragm MEP amplitude depression during NIV is related to neuromechanical inhibition at the level of motor cortex. Our results demonstrate that mechanical ventilation directly inhibits central projections to the diaphragm.

It is unknown whether changes in corticomotor excitability follow exercise in healthy humans. We hypothesized that a fall in the diaphragm and quadriceps motor- evoked potential ( MEP) amplitude elicited by transcranial magnetic stimulation of the motor cortex would occur after an incremental exercise task. In 11 healthy subjects, we measured transdiaphragmatic pressure and isometric quadriceps tension in response to supramaximal peripheral magnetic nerve stimulation. MEPs were recorded from these muscles in response to transcranial magnetic stimulation. After baseline measurements, subjects performed a period of submaximal exercise ( gentle walking). Measurements were repeated 5 and 20 min after this. The subjects then exercised on a treadmill with an incremental protocol to exhaustion. Transcranial magnetic stimulation was performed at baseline and at 5, 20, 40, and 60 min after exhaustive exercise, and force measurements were obtained at baseline, 20 min, and 60 min. Mean exercise duration was 18 +/- 4 min, and mean maximum heart rate was 172 +/- 10 beats/ min. Twitch transdiaphragmatic pressure and twitch isometric quadriceps tension were not different from baseline after exercise, but a significant decrease was observed in diaphragm MEP amplitude 5 and 20 min after exercise ( 60 +/- 38 and 45 +/- 24%, respectively, of baseline, P = 0.0001). At the same times, the mean quadriceps MEPs were 59 +/- 39 and 74 +/- 32% of baseline ( P < 0.0001 and P < 0.01, respectively). Studies using paired stimuli confirmed a likely intracortical mechanism for this depression. Our data confirm significant depression of both diaphragm and quadriceps MEPs after incremental treadmill exercise.

Patients with chronic obstructive pulmonary disease (COPD) face an increased respiratory load and in consequence have an elevated respiratory drive. We used transcranial magnetic stimulation (TMS) to investigate associated changes in corticospinal excitability both at rest and during voluntary facilitation at different levels of inspiratory effort. Diaphragm and abdominal motor thresholds were significantly lower in COPD than healthy controls, but the quadriceps response was the same. In patients there was a significant increase in diaphragm response from rest during 20% inspiratory efforts but no further increase with greater efforts. In controls there was a further stepwise increase at 40% and 60% of inspiratory effort. The cortical silent period was significantly shorter in COPD. Using paired stimulation to study intracortical inhibitory and excitatory circuits we found significantly less excitability of intracortical facilitatory circuits in patients at long (>7 ms) interstimulus intervals. These results suggest that there is a ceiling effect in motor control output to the respiratory muscles of patients with COPD.

Adults and children with neuromuscular disease exhibit weak cough and are susceptible to recurrent chest infections, a major cause of morbidity and mortality. Mechanical insufflation/exsufflation may improve cough efficacy by increasing peak cough flow. It was hypothesised that mechanical insufflation/exsufflation would produce a greater increase in peak cough flow than other modes of cough augmentation. The acceptability of these interventions was also compared.Twenty-two patients aged 10–56 yrs (median 21 yrs) with neuromuscular disease and 19 age-matched controls were studied. Spirometry was performed and respiratory muscle strength measured. Peak cough flow was recorded during maximal unassisted coughs, followed in random order by coughs assisted by physiotherapy, noninvasive ventilation, insufflation and exsufflation, and exsufflation alone. Subjects rated strength of cough, distress and comfort on a visual analogue scale.In the neuromuscular disease group, mean±sd forced expiratory volume in one second was 0.8±0.6 L·s−1, forced vital capacity 0.9±0.8 L, maximum inspiratory pressure 25±16 cmH2O, maximum expiratory pressure 26±22 cmH2O and unassisted peak cough flow 169±90 L·min−1. The greatest increase in peak cough flow was observed with mechanical insufflation/exsufflation at 235±111 L·min−1(p<0.01). All techniques showed similar patient acceptability.Mechanical insufflation/exsufflation produces a greater increase in peak cough flow than other standard cough augmentation techniques in adults and children with neuromuscular disease.

Background Results of experimental and clinical studies have shown that septic shock is associated with cardiovascular autonomic failure. Thus, we aimed to investigate the existence of ischaemia and apoptosis within the cerebral autonomic centres that control the cardiovascular system in patients with septic shock.Methods In a prospective cohort study, we did post-mortem examinations of supraoptic and paraventricular nuclei, cerebral amygdala, locus coeruleus, and medullary autonomic nuclei in 19 patients with septic shock, seven with non-septic shock and five who died suddenly from extracranial injury. Ischaemic and apoptotic neurons and microglial cells, and expression of tumour necrosis factor alpha (TNFalpha) and inducible nitric oxide synthase (iNOS) were scored.Findings Ischaemic, neuronal, and microglial apoptosis scores differed between groups (p=0.0007, p<0.0001, and p=0.0037, respectively) and were higher in patients with septic shock than in those with non-septic shock (p=0.0033, p=0.0005, and p=0.0235, respectively), and extra-cranial injury related deaths (p=0.0027, p=0.0007, and p=0.0045, respectively). There was little microglial activation and glial expression of TNF alpha. The scores for endothelial iNOS expression were different between the three groups (p<0.0001), and were higher in septic shock than in nonseptic shock (p=0.0009) and than in extracranial injury related deaths (p=0.0007). Vascular expression of iNOS also correlated (Spearman tau=0.57) with autonomic-centre neuronal apoptosis in the combined septic and non-septic shock group.Interpretation Septic shock is associated with neuronal and glial apoptosis within the autonomic centres, which is strongly associated with endothelial iNOS expression.

We assessed recruitment curves of the surface diaphragm motor-evoked potential (MEP) after transcranial magnetic stimulation during relaxation and at three different levels of facilitation (20, 40, and 60% of maximal inspiratory esophageal pressure) in 10 healthy subjects (six young and four elderly). MEP amplitude recruitment curves varied between individuals during relaxation and at each level of facilitation. Amplitude recruitment curves during relaxation were reproducible in individual subjects. Inspiratory maneuvers caused a decrease in motor threshold and latency and an increase in MEP amplitude, positively correlated to the intensity of facilitation. These changes were similar in young and elderly subjects. The best fit for MEP amplitude recruitment curves for each condition was obtained with a Boltzmann model. The performance of repeated submaximal inspiratory maneuvers did not affect the amplitude recruitment curves of the relaxed diaphragm. We conclude that the recruitment curve of the diaphragm with transcranial magnetic stimulation is repeatable and changes consistently with facilitation and will, therefore, be a robust experimental tool for the investigation of supraspinal pathways to the diaphragm.