Ewen Ross

Apoptosis of neurons in cardiovascular autonomic centres triggered by inducible nitric oxide synthase after death from septic shock

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 TNFalpha. The scores for endothelial iNOS expression were different between the three groups (p<0.0001), and were higher in septic shock than in non-septic 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.

Endobronchial coils for the treatment of severe emphysema with hyperinflation (RESET): a randomised controlled trial

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 Georges 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. FUNDING PneumRx.

Corticospinal control of respiratory muscles in chronic obstructive pulmonary disease

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.

Endobronchial Coils for Severe Emphysema Are Effective Up to 12 Months following Treatment: Medium Term and Cross-Over Results from a Randomised Controlled Trial

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.

Intracortical inhibition and facilitation of the response of the diaphragm to transcranial magnetic stimulation

&NA; Respiratory muscles respond to a subcortical automatic command and to a neocortical voluntary command. In diseases such as stroke or motor neurone disease, an abnormal diaphragmatic response to single transcranial magnetic stimuli can identify a central source for respiratory disorders, but this is not likely to be the case in disorders affecting intracortical inhibitory and facilitatory mechanisms. This study describes the response of the diaphragm to paired transcranial magnetic stimulation. Thirteen normal subjects were studied (age range, 22 to 43 years; 7 men; phrenic conduction, <6.8 msec; latency of diaphragmatic motor evoked potential, <20.5 msec). Motor evoked potentials in response to paired stimulation were obtained in eight subjects only, with the motor threshold in the remaining five subjects too high to absorb the loss of power inherent in the double‐stimulation montage. Interstimulus intervals less than 5 msec resulted in a statistically significant inhibition (p < 0.01 for interstimulus intervals of 1 and 3 ms), whereas intervals longer than 6 msec were facilitatory (maximal, 15 msec). The diaphragmatic pattern matched that of the biceps brachii. The authors conclude that it is possible to study intracortical inhibition and facilitation of diaphragmatic control, although not in all subjects. Technical improvement should alleviate current limitations and make paired transcranial magnetic stimulation a tool to study respiratory muscle abnormalities in settings in which intracortical interactions are important, such as movement disorders.

Does symptom-limited cycle exercise cause low frequency diaphragm fatigue in patients with heart failure?

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.

Motor control of the costal and crural diaphragm – insights from transcranial magnetic stimulation in man

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.

Exercise-induced depression of the diaphragm motor evoked potential is not affected by non-invasive ventilation

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.

S53 Outcomes of the RePneu Endobronchial Coils For the Treatment of Severe Emphysema with HyperinflaTion (RESET) Trial

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. Abstract S53 Table 1 Primary and Secondary Efficacy Outcomes in the Intent-to-Treat Population (Change from Baseline at 90 Days post Final Treatment) RePneu Coil Treatment (n=23) Control (n=24) Between-Group Difference in Change from Baseline P-value number (95% confidence interval) Initial Analysis† Primary outcome  Mean change in SGRQ –9.11 (–14.59 to –3.62) 1.43 (–4.05 to 6.92) –10.54 (–17.52 to –3.56) 0.004 Secondary outcome  Mean change in TLC (L) –0.36 (–0.55 to –0.18) –0.25 (–0.43 to –0.07) –0.11 (–0.35 to 0.12) 0.330  Mean change in RV (L) –0.64 (0.92 to –0.37) –0.29 (–0.57 to –0.02) –0.35 (–0.70 to 0.00) 0.051  Mean change in 6-minute Walk Test (m) 52.98 (29.18 to 76.78) –17.41 (–41.21 to 6.39) 70.39 (40.10 to 100.68) <0.001‡  Mean percent change in FEV1 14.85 (7.46 to 22.23) 2.04 (–5.35 to 9.42) 12.81 (3.41 to 22.21) 0.009‡ SGRQ denotes St. George’s Respiratory Questionnaire, TLC total lung capacity, RV residual volume, and FEV1 forced expiratory volume in 1 second. † P-value determined by analysis of variance (ANOVA) with factors of treatment and site. ‡ Statistical significance via the Hochberg adjustment for multiplicity for secondary outcomes.