Caroline Jolley

An integrated palliative and respiratory care service for patients with advanced disease and refractory breathlessness: a randomised controlled trial

BACKGROUND Breathlessness is a common and distressing symptom, which increases in many diseases as they progress and is difficult to manage. We assessed the effectiveness of early palliative care integrated with respiratory services for patients with advanced disease and refractory breathlessness. METHODS In this single-blind randomised trial, we enrolled consecutive adults with refractory breathlessness and advanced disease from three large teaching hospitals and via general practitioners in South London. We randomly allocated (1:1) patients to receive either a breathlessness support service or usual care. Randomisation was computer generated centrally by the independent Clinical Trials Unit in a 1:1 ratio, by minimisation to balance four potential confounders: cancer versus non-cancer, breathlessness severity, presence of an informal caregiver, and ethnicity. The breathlessness support service was a short-term, single point of access service integrating palliative care, respiratory medicine, physiotherapy, and occupational therapy. Research interviewers were masked as to which patients were in the treatment group. Our primary outcome was patient-reported breathlessness mastery, a quality of life domain in the Chronic Respiratory Disease Questionnaire, at 6 weeks. All analyses were by intention to treat. Survival was a safety endpoint. This trial is registered with ClinicalTrials.gov, number NCT01165034. FINDINGS Between Oct 22, 2010 and Sept 28, 2012, 105 consenting patients were randomly assigned (53 to breathlessness support service and 52 to usual care). 83 of 105 (78%) patients completed the assessment at week 6. Mastery in the breathlessness support service group improved compared with the control (mean difference 0·58, 95% CI 0·01-1·15, p=0·048; effect size 0·44). Sensitivity analysis found similar results. Survival rate from randomisation to 6 months was better in the breathlessness support service group than in the control group (50 of 53 [94%] vs 39 of 52 [75%]) and in overall survival (generalised Wilcoxon 3·90, p=0·048). Survival differences were significant for patients with chronic obstructive pulmonary disease and interstitial lung disease but not cancer. INTERPRETATION The breathlessness support service improved breathlessness mastery. Our findings provide robust evidence to support the early integration of palliative care for patients with diseases other than cancer and breathlessness as well as those with cancer. The improvement in survival requires further investigation. FUNDING UK National Institute for Health Research (NIHR) and Cicely Saunders International.

Outpatient pulmonary rehabilitation following acute exacerbations of COPD

Background Exacerbations of chronic obstructive pulmonary disease (COPD) are characterised by increased dyspnoea, reduced quality of life and muscle weakness. Re-exacerbation and hospital admission are common. Pulmonary rehabilitation (PR) administered after hospital admission for an exacerbation can improve quality of life and exercise capacity. Objective To determine whether outpatient post-exacerbation PR (PEPR) could reduce subsequent hospital admission episodes. Methods Patients admitted to hospital for an exacerbation of COPD were randomised to receive either usual follow-up care (UC) or PEPR after discharge. Hospital admission and emergency department attendances for COPD exacerbations were recorded over a 3-month period and analysed on an intention-to-treat basis. Secondary outcomes included exercise capacity and quadriceps strength. Results 60 patients underwent concealed randomisation at the time of their hospital discharge (UC: n=30, mean (SD) age 65 (10) years, forced expiratory volume in 1 s (FEV1) 52 (22)% predicted; PEPR: n=30, 67(10) years, 52 (20)% predicted). The proportion of patients re-admitted to hospital with an exacerbation was 33% in the UC group compared with 7% in those receiving PEPR (OR 0.15, 95% CI 0.03 to 0.72, p=0.02). The proportion of patients that experienced an exacerbation resulting in an unplanned hospital attendance (either admission or review and discharge from the emergency department) was 57% in the UC group and 27% in those receiving PEPR (OR 0.28, 95% CI 0.10 to 0.82, p=0.02). Conclusions Post-exacerbation rehabilitation in COPD can reduce re-exacerbation events that require admission or hospital attendance over a 3-month period. Clinical Trials Registration Number NCT00557115.

Ultrasound measurement of rectus femoris cross-sectional area and the relationship with quadriceps strength in COPD

Background: Quadriceps weakness and loss of muscle mass predict mortality in chronic obstructive pulmonary disease (COPD). It was hypothesised that a reduced quadriceps cross-sectional area could be detected by ultrasound in patients with COPD compared with healthy subjects, and that measurements relate to strength and fat-free mass (FFM). Methods: Rectus femoris muscle cross-sectional area (RFCSA) was measured by ultrasound and whole-body FFM estimated using electrical bioimpedance. Quadriceps strength was measured by maximum voluntary contraction and twitch tension (TwQ) following magnetic femoral nerve stimulation. Results: 26 healthy volunteers of mean (SD) age 63 (9) years and 30 patients with COPD of mean (SD) age 67 (9) years and percentage predicted forced expiratory volume in 1 s (FEV1) 48.0 (20.8)% with a similar FFM (46.9 (9.3) kg vs 46.1 (7.3) kg, p = 0.193) participated in the study. Mean RFCSA was reduced in patients with COPD by 25% of the mean value in healthy subjects(−115 mm2; 95% CI −177 to −54, p = 0.001) and was related to MRC dyspnoea scale score, independent of FFM or sex. Maximum voluntary contraction strength was linearly related to RFCSA in patients with COPD (r = 0.78, p<0.001). TwQ force per unit of RFCSA was similar in both healthy individuals and those with COPD (mean (SD) 17 (4) g/mm2 vs 18 (3) g/mm2, p = 0.657). Voluntary contraction strength per unit of RFCSA was dependent on central quadriceps activation and peripheral oxygen saturation in COPD. Conclusion: Ultrasound measurement of RFCSA is an effort-independent and radiation-free method of measuring quadriceps muscle cross-sectional area in patients with COPD that relates to strength.

The value of multiple tests of respiratory muscle strength

Background: Respiratory muscle weakness is an important clinical problem. Tests of varying complexity and invasiveness are available to assess respiratory muscle strength. The relative precision of different tests in the detection of weakness is less clear, as is the value of multiple tests. Methods: The respiratory muscle function tests of clinical referrals who had multiple tests assessed in our laboratories over a 6-year period were analysed. Thresholds for weakness for each test were determined from published and in-house laboratory data. The patients were divided into three groups: those who had all relevant measurements of global inspiratory muscle strength (group A, n = 182), those with full assessment of diaphragm strength (group B, n = 264) and those for whom expiratory muscle strength was fully evaluated (group C, n = 60). The diagnostic outcome of each inspiratory, diaphragm and expiratory muscle test, both singly and in combination, was studied and the impact of using more than one test to detect weakness was calculated. Results: The clinical referrals were primarily for the evaluation of neuromuscular diseases and dyspnoea of unknown cause. A low maximal inspiratory mouth pressure (Pimax) was recorded in 40.1% of referrals in group A, while a low sniff nasal pressure (Sniff Pnasal) was recorded in 41.8% and a low sniff oesophageal pressure (Sniff Poes) in 37.9%. When assessing inspiratory strength with the combination of all three tests, 29.6% of patients had weakness. Using the two non-invasive tests (Pimax and Sniff Pnasal) in combination, a similar result was obtained (low in 32.4%). Combining Sniff Pdi (low in 68.2%) and Twitch Pdi (low in 67.4%) reduced the diagnoses of patients with diaphragm weakness to 55.3% in group B. 38.3% of the patients in group C had expiratory muscle weakness as measured by maximum expiratory pressure (Pemax) compared with 36.7% when weakness was diagnosed by cough gastric pressure (Pgas), and 28.3% when assessed by Twitch T10. Combining all three expiratory muscle tests reduced the number of patients diagnosed as having expiratory muscle weakness to 16.7%. Conclusion: The use of single tests such as Pimax, Pemax and other available individual tests of inspiratory, diaphragm and expiratory muscle strength tends to overdiagnose weakness. Combinations of tests increase diagnostic precision and, in the population studied, they reduced the diagnosis of inspiratory, specific diaphragm and expiratory muscle weakness by 19–56%. Measuring both Pimax and Sniff Pnasal resulted in a relative reduction of 19.2% of patients falsely diagnosed with inspiratory muscle weakness. The addition of Twitch Pdi to Sniff Pdi increased diagnostic precision by a smaller amount (18.9%). Having multiple tests of respiratory muscle function available both increases diagnostic precision and makes assessment possible in a range of clinical circumstances.

Neural Respiratory Drive in Obesity

Background: The load imposed on ventilation by increased body mass contributes to the respiratory symptoms caused by obesity. A study was conducted to quantify ventilatory load and respiratory drive in obesity in both the upright and supine postures. Methods: Resting breathing when seated and supine was studied in 30 obese subjects (mean (SD) body mass index (BMI) 42.8 (8.6) kg/m2) and 30 normal subjects (mean (SD) BMI 23.6 (3.7) kg/m2), recording the electromyogram of the diaphragm (EMGdi, transoesophageal multipair electrode), gastric and oesophageal pressures. Results: Ventilatory load and neural drive were higher in the obese group as judged by the EMGdi (21.9 (9.0) vs 8.4 (4.0)%max, p<0.001) and oesophageal pressure swings (9.6 (2.9) vs 5.3 (2.2) cm H2O, p<0.001). The supine posture caused an increase in oesophageal pressure swings to 16.0 (5.0) cm H2O in obese subjects (p<0.001) and to 6.9 (2.0) cm H2O in non-obese subjects (p<0.001). The EMGdi increased in the obese group to 24.7 (8.2)%max (p<0.001) but remained the same in non-obese subjects (7.0 (3.4)%max, p = NS). Obese subjects developed intrinsic positive end-expiratory pressure (PEEPi) of 5.3 (3.6) cm H2O when supine. Applying continuous positive airway pressure (CPAP) in a subgroup of obese subjects when supine reduced the EMGdi by 40%, inspiratory pressure swings by 25% and largely abolished PEEPi (4.1 (2.7) vs 0.8 (0.4) cm H2O, p = 0.009). Conclusion: Obese patients have substantially increased neural drive related to BMI and develop PEEPi when supine. CPAP abolishes PEEPi and reduces neural respiratory drive in these patients. These findings highlight the adverse respiratory consequences of obesity and have implications for the clinical management of patients, particularly where the supine posture is required.

Neural respiratory drive in healthy subjects and in COPD

The aim of the present study was to use the diaphragm electromyogram (EMGdi) to compare levels of neural respiratory drive (NRD) in a cohort of healthy subjects and chronic obstructive pulmonary disease (COPD) patients, and to investigate the relationship between NRD and pulmonary function in COPD. EMGdi was recorded at rest and normalised to peak EMGdi recorded during maximum inspiratory manoeuvres (EMGdi % max) in 100 healthy subjects and 30 patients with COPD, using a multipair oesophageal electrode. EMGdi was normalised to the amplitude of the diaphragm compound muscle action potential (CMAPdi,MS) in 64 healthy subjects. The mean±sd EMGdi % max was 9.0±3.4% in healthy subjects and 27.9±9.9% in COPD patients, and correlated with percentage predicted forced expiratory volume in one second, vital capacity and inspiratory capacity in patients. EMGdi % max was higher in healthy subjects aged 51–80 yrs than in those aged 18–50 yrs (11.4±3.4 versus 8.2±2.9%, respectively). Observations in the healthy group were similar when peak EMGdi or CMAPdi,MS were used to normalise EMGdi. Levels of neural respiratory drive were higher in chronic obstructive pulmonary disease patients than healthy subjects, and related to disease severity. Diaphragm compound muscle action potential could be used to normalise diaphragm electromyogram if volitional inspiratory manoeuvres could not be performed, allowing translation of the technique to critically ill and ventilated patients.

Researching breathlessness in palliative care: consensus statement of the National Cancer Research Institute Palliative Care Breathlessness Subgroup.

Breathlessness is common in advanced disease and can have a devastating impact on patients and carers. Research on the management of breathlessness is challenging. There are relatively few studies, and many studies are limited by inadequate power or design. This paper represents a consensus statement of the National Cancer Research Institute Palliative Care Breathlessness Subgroup. The aims of this paper are to facilitate the design of adequately powered multi-centre interventional studies in breathlessness, to suggest a standardised, rational approach to breathlessness research and to aid future ‘between study’ comparisons. Discussion of the physiology of breathlessness is included.

Neural respiratory drive, pulmonary mechanics and breathlessness in patients with cystic fibrosis

Background Neural respiratory drive (NRD) measured from the diaphragm electromyogram (EMGdi) reflects the load/capacity balance of the respiratory muscle pump and is a marker of lung disease severity. EMGdi measurement is invasive, but recording the EMG from the parasternal intercostal muscles using surface electrodes (sEMGpara) could provide a non-invasive method of assessing NRD and disease severity. Objectives To test the hypothesis that NRD measured by sEMGpara correlates with EMGdi, to provide an index of disease severity in cystic fibrosis (CF) and to relate to exercise-induced breathlessness. Methods 15 patients with CF (mean forced expiratory volume in 1 s (FEV1) 53.5% predicted) and 15 age-matched healthy controls were studied. sEMGpara and EMGdi were recorded at rest and during exercise. sEMGpara was recorded using surface electrodes and EMGdi using a multipair oesophageal electrode catheter. Signals were normalised using the peak EMG recorded during maximum respiratory manoeuvres and expressed as EMG%max. The respiratory pattern, metabolic data, oesophageal and gastric pressures and Borg scores were also recorded. Results Mean (SD) resting sEMGpara%max and EMGdi%max were higher in patients with CF than in controls (13.1 (7)% and 18.5 (7.5)% vs 5.8 (3)% and 7.5 (2)%, respectively, p<0.001). In the patients with CF, resting sEMGpara%max and EMGdi%max were related to the degree of airways obstruction (FEV1) (r=−0.91 and r=−0.82, both p<0.001), hyperinflation (r=0.63 and r=0.56, both p<0.001) and dynamic lung compliance (r=−0.53 and r=−0.59, both p<0.001). During exercise, sEMGpara%max and EMGdi%max were strongly correlated with breathlessness in the patients with CF before (r=0.906, p<0.001) and after (r=0.975, p<0.001) the onset of neuromechanical dissociation. Conclusion sEMGpara%max provides a non-invasive marker of neural drive, which reflects disease severity and exercise-induced breathlessness in CF.

Neural respiratory drive as a physiological biomarker to monitor change during acute exacerbations of COPD

Background Acute exacerbations of chronic obstructive pulmonary disease have a significant negative impact on both patients and healthcare systems. Currently, there are no physiological biomarkers that effectively monitor clinical change or predict respiratory readmission. Acute exacerbations impose a change in the respiratory muscle load-capacity-drive relationship. It was hypothesised that lack of a fall in neural respiratory drive would identify patients at risk of treatment failure and early hospital readmission. Methods An observational study was performed at two UK teaching hospitals. Routine clinical physiological parameters and neural respiratory drive index (NRDI), calculated as the product of second intercostal space parasternal electromyography (EMG) activity normalised to the peak EMG activity during a maximum inspiratory sniff manoeuvre and respiratory rate, were recorded daily from admission to discharge. Results 30 acutely unwell patients of mean (SD) age 72 (10) years, forced expiratory volume in 1 s 0.60 (1.65) l, NRDI 455 (263) AU and median length of stay 6 days were studied. Changes in NRDI correlated with changes in Borg score (r=+0.60; p<0.001), discriminated between patients deemed to have clinically improved rather than deteriorated (mean difference 339 AU; 95% CI 234 to 444; p<0.001) and identified those patients readmitted within 14 days (mean difference 203 AU; 95% CI 39 to 366; p=0.017). Conclusions NRDI is a feasible clinical physiological parameter in patients with an acute exacerbation of chronic obstructive pulmonary disease and can provide useful information on treatment response and risk of readmission.

Acute ischaemic hemispheric stroke is associated with impairment of reflex in addition to voluntary cough

Cough function is impaired after stroke; this may be important for protection against chest infection. Reflex cough (RC) intensity indices have not been described after stroke. RC, voluntary cough (VC) and respiratory muscle strength were studied in patients within 2 weeks of hemispheric infarct. The null hypotheses were that patients with cortical hemisphere stroke would show the same results as healthy controls on: 1) objective indices of RC and VC intensity; and 2) respiratory muscle strength tests. Peak cough flow rate (PCFR) and gastric pressure (Pga) were measured during maximum VC and RC. Participants also underwent volitional and nonvolitional respiratory muscle testing. Nonvolitional expiratory muscle strength was assessed by measuring Pga increase after magnetic stimulation over the T10 nerve roots (twitch T10 Pga). Stroke severity was scored using the National Institutes of Health Stroke Scale (NIHSS; maximum = 31). 18 patients (mean±sd age 62±15 yrs and NIHSS score 14±8) and 20 controls (56±16 yrs) participated. VC intensity was impaired in patients (PCFR 287±171 versus 497±122 L·min−1) as was VC Pga (98.5±61.6 versus 208.5±61.3 cmH2O; p<0.001 for both). RC PCFR was reduced in patients (204±111 versus 379±110 L·min−1; p<0.001), but RC Pga was not significantly different from that of controls (179.0±78.0 versus 208.0±77.4 cmH2O; p = 0.266). Patients exhibited impaired volitional respiratory muscle tests, but twitch T10 Pga was normal. VC and RC are both impaired in hemispheric stroke patients, despite preserved expiratory muscle strength. Cough coordination is probably cortically modulated and affected by hemispheric stroke.