Undetected Respiratory Depression in People with Opioid Use Disorder.

BACKGROUND: Opioid-related deaths are increasing globally. Respiratory complications of opioid use and underlying respiratory disease in people with Opioid Use Disorder (OUD) are potential contributory factors. Individual variation in susceptibility to overdose is, however, incompletely understood. This study investigated the prevalence of respiratory depression (RD) in OUD treatment and compared this to patients with chronic obstructive pulmonary disease (COPD) of equivalent severity. We also explored the contribution of opioid agonist treatment (OAT) dosage, and type, to the prevalence of RD. METHODS: There were four groups of participants: 1) OUD plus COPD ('OUD-COPD', n = 13); 2) OUD without COPD ('OUD', n = 7); 3) opioid-naïve COPD patients ('COPD'n = 13); 4) healthy controls ('HC'n = 7). Physiological indices, including pulse oximetry (SpO2%), end-tidal CO2 (ETCO2), transcutaneous CO2 (TcCO2), respiratory airflow and second intercostal space parasternal muscle electromyography (EMGpara), were recorded continuously over 40 min whilst awake at rest. Significant RD was defined as: SpO2%< 90% for > 10 s, ETCO2 per breath > 6.6 kPa, TcCO2 overall mean > 6 kPa, respiratory pauses > 10 s RESULTS: At least one indicator was observed in every participant with OUD (n = 20). This compared to RD episode occurrence in only 2/7 HC and 2/13 COPD participants (p < 0.05,Fisher's exact test). The occurrence of RD was similar in OUD participants prescribed methadone (n = 6) compared to those prescribed buprenorphine (n = 12). CONCLUSIONS: Undetected RD is common in OUD cohorts receiving OAT and is significantly more severe than in opioid-naïve controls. RD can be assessed using simple objective measures. Further studies are required to determine the association between RD and overdose risk.

COPD and asthma in patients with opioid dependency: a cross-sectional study in primary care.

Patients treated for drug addiction have high asthma and COPD prevalence rates. The relative contributions of cigarette smoking, smoking intensity and possible smoking of other substances has not been described. We aimed to describe the prevalence and determinants of asthma and COPD in patients prescribed methadone as opioid substitution therapy (OST). In a cross-sectional study of an anonymised patient-level primary care dataset of UK inner-city general practices (n = 46), 321,395 patients aged ≥18 years were identified. A total of 676 (0.21%) had a record of a methadone ever issued in primary care. The association between respiratory disease and methadone prescribing was examined using logistic regression. Models were adjusted for potential effects of clustering by practice. A total of 97.3% of patients prescribed methadone were cigarette smokers, either current (81.2%) or ex-smokers (16.1%). The prevalences of asthma and COPD were higher in methadone patients (14.2% and 12.4%, respectively) compared to non-methadone patients (4.4% and 1.1%, respectively). Methadone was an independent determinant of asthma, adjusting for smoking status (OR 3.21; 95% CI: 2.52, 4.10) or for smoking intensity (3.08; 2.27, 4.19), and of COPD, adjusting for smoking status (6.00; 4.61, 7.80) or for smoking intensity (5.80; 4.12, 8.17). COPD and asthma prevalence were substantially higher in those prescribed methadone compared to those never prescribed methadone. Prescription of methadone was an independent predictor for both COPD and asthma, even after adjustment for smoking status and smoking intensity. Possible explanations include confounding by association with smoking of heroin or crack cocaine, both of which may have a causal association with COPD and asthma.

Mirtazapine for chronic breathlessness? A review of mechanistic insights and therapeutic potential.

INTRODUCTION: Chronic breathlessness is a common and distressing symptom of advanced disease with few effective treatments. Central nervous system mechanisms are important in respiratory sensation and control. Consequently, drugs which may modify processing and perception of afferent information in the brain may have a role. Antidepressants have been proposed; however, current evidence is limited. Of potentially suitable antidepressants, mirtazapine is an attractive option given its tolerability profile, low cost, and wide availability, along with additional potential benefits. Areas covered: The paper provides an overview of the physiology of breathlessness, with an emphasis on central mechanisms, particularly the role of fear circuits and the associated neurotransmitters. It provides a potential rationale for how mirtazapine may improve chronic breathlessness and quality of life in patients with advanced disease. The evidence was identified by a literature search performed in PubMed through to October 2018. Expert opinion: Currently, there is insufficient evidence to support the routine use of antidepressants for chronic breathlessness in advanced disease. Mirtazapine is a promising candidate to pursue, with definitive randomized controlled trials required to determine its efficacy and safety in this setting.

Medication-taking behaviours in young adults with schizophrenia: a pilot study.

The purpose of this prospective and observational study was to explore medication-taking behaviours in community-based young adults with schizophrenia using an electronic monitoring system and patient self-report questionnaires. The Medication Event Monitoring System (MEMS®), the Index for Medication Adherence (IMA) and the Brief Evaluation of Medication Influences and Beliefs (BEMIB) measured medication-taking behaviours. Data were collected at baseline, 4 and 8 weeks. Descriptive statistics were used in analysis. A total of 11 subjects were recruited; one dropped out. Five were male, and five were female. Average age was 32.64 (SD = 5.70) years. Four (40%) were White people; six (60%) were non-White people. The average number of medications treating schizophrenia was 1.9 (SD = 0.57). MEMS® identified 71.77% (SD = 30.47) dose adherence and 55.92% (SD = 31.27) day adherence. Most subjects took medications irregularly (early, late or missing). The BEMIB demonstrated that 50%, 20% and 30% of subjects considered themselves to be adherent to their medications at baseline, 4 weeks and 8 weeks, while the IMA reported 90%, 90% and 80% at baseline, 4 weeks and 8 weeks, respectively. Regarding the observed discrepancies between patients' reports and their actual medication-taking behaviours, clinical implications were discussed. Effective interventions improving medication adherence in schizophrenia are needed for practice and for future studies.

Screening for sleep-disordered breathing in neuromuscular disease using a questionnaire for symptoms associated with diaphragm paralysis.

Patients with neuromuscular disease (NMD) are at risk of developing sleep-disordered breathing (SDB) following respiratory muscle involvement. We hypothesised that a questionnaire based on clinical symptoms and signs of diaphragm weakness can be used to screen for SDB in such patients. We developed a self-administered multiple choice questionnaire containing five questions (Sleep-Disordered Breathing in Neuromuscular Disease Questionnaire (SiNQ)-5), scoring 0-10 points. 125 patients were enrolled: 32 with respiratory muscle weakness, 35 subjects with normal respiratory muscle strength and 58 patients with obstructive sleep apnoea (OSA). All subjects underwent full polysomnography. NMD patients with involvement of the respiratory muscles scored mean ± sd 6.8 ± 2.3 out of 10 points, significantly higher than both OSA patients 2.5 ± 2.3 and normal subjects 1.0 ± 2.0 (p < 0.001). A score of five or more points in the SiNQ-5 had a sensitivity of 86.2%, specificity of 88.5%, positive predictive value of 69.4% and a negative predictive value of 95.5% to identify NMD with combined SDB. A short self-administered questionnaire, the SiNQ-5, based on clinical symptoms can reliably screen for SDB in patients with diaphragm weakness. However, comorbidities, such as heart failure, that have symptoms influenced by posture could alter diagnostic accuracy.

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 (P(ga)) were measured during maximum VC and RC. Participants also underwent volitional and nonvolitional respiratory muscle testing. Nonvolitional expiratory muscle strength was assessed by measuring P(ga) increase after magnetic stimulation over the T10 nerve roots (twitch T10 P(ga)). 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 P(ga) (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 P(ga) 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 P(ga) 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.

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/m(2)) and 30 normal subjects (mean (SD) BMI 23.6 (3.7) kg/m(2)), 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 H(2)O, p<0.001). The supine posture caused an increase in oesophageal pressure swings to 16.0 (5.0) cm H(2)O in obese subjects (p<0.001) and to 6.9 (2.0) cm H(2)O 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 H(2)O 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 H(2)O, 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.

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 (RF(CSA)) 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 (FEV(1)) 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 RF(CSA) was reduced in patients with COPD by 25% of the mean value in healthy subjects(-115 mm(2); 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 RF(CSA) in patients with COPD (r = 0.78, p<0.001). TwQ force per unit of RF(CSA) was similar in both healthy individuals and those with COPD (mean (SD) 17 (4) g/mm(2) vs 18 (3) g/mm(2), p = 0.657). Voluntary contraction strength per unit of RF(CSA) was dependent on central quadriceps activation and peripheral oxygen saturation in COPD. CONCLUSION: Ultrasound measurement of RF(CSA) is an effort-independent and radiation-free method of measuring quadriceps muscle cross-sectional area in patients with COPD that relates to strength.

Neural respiratory drive in healthy subjects and in COPD.

The aim of the present study was to use the diaphragm electromyogram (EMG(di)) 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. EMG(di) was recorded at rest and normalised to peak EMG(di) recorded during maximum inspiratory manoeuvres (EMG(di) % max) in 100 healthy subjects and 30 patients with COPD, using a multipair oesophageal electrode. EMG(di) was normalised to the amplitude of the diaphragm compound muscle action potential (CMAP(di,MS)) in 64 healthy subjects. The mean+/-sd EMG(di) % 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. EMG(di) % 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 EMG(di) or CMAP(di,MS) were used to normalise EMG(di). 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.

A physiological model of patient-reported breathlessness during daily activities in COPD.

Breathlessness during daily activities has a significant impact on quality of life in chronic obstructive pulmonary disease. Herein, we present a physiological model of patient-reported breathlessness based on the relationship between ventilatory load, respiratory muscle capacity, neural respiratory drive and neuromechanical dissociation during daily activities. This model should facilitate an understanding of the mechanisms driving increased intensity of breathlessness during daily activities and the relief of breathlessness following medical or surgical interventions. The model should also provide a structure on which to base the development of patient-reported outcome instruments to measure the severity of breathlessness during daily activities in chronic obstructive pulmonary disease.

Sleep-disordered breathing in unilateral diaphragm paralysis or severe weakness.

Few data exist concerning sleep in patients with hemidiaphragm paralysis or weakness. Traditionally, such patients are considered to sustain normal ventilation in sleep. In the present study, diaphragm strength was measured in order to identify patients with unilateral paralysis or severe weakness. Patients underwent polysomnography with additional recordings of the transoesophageal electromyogram (EMG) of the diaphragm and surface EMG of extra-diaphragmatic respiratory muscles. These data were compared with 11 normal, healthy subjects matched for sex, age and body mass index (BMI). In total, 11 patients (six males, mean+/-sd age 56.5+/-10.0 yrs, BMI 28.7+/-2.8 kg x m(-2)) with hemidiaphragm paralysis or severe weakness (unilateral twitch transdiaphragmatic pressure 3.3+/-1.7 cmH(2)O (0.33+/-0.17 kPa) were studied. They had a mean+/-sd respiratory disturbance index of 8.1+/-10.1 events x h(-1) during non-rapid eye movement (NREM) sleep and 26.0+/-17.8 events x h(-1) during rapid eye movement (REM) sleep (control groups 0.4+/-0.4 and 0.7+/-0.9 events x h(-1), respectively). The diaphragm EMG, as a percentage of maximum, was double that of the control group in NREM sleep (15.3+/-5.3 versus 8.9+/-4.9% max, respectively) and increased in REM sleep (20.0+/-6.9% max), while normal subjects sustained the same level of activation (6.2+/-3.1% max). Patients with unilateral diaphragm dysfunction are at risk of developing sleep-disordered breathing during rapid eye movement sleep. The diaphragm electromyogram, reflecting neural respiratory drive, is doubled in patients compared with normal subjects, and increases further in rapid eye movement sleep.

Electrophysiological evidence for retinal projections to the hypothalamic supraoptic nucleus and its perinuclear zone.

Secretion of vasopressin (VP) and oxytocin (OT) displays a daily rhythm. Using electrophysiological methods, we investigated the projections from the optic nerve to the supraoptic nucleus (SON) and its perinuclear zone (PNZ) which might underlie the rhythm. Extracellular recordings were made from magnocellular cells in the SON and its PNZ in 22 urethane-anaesthetized female Wistar rats while stimulating the optic nerve. The responses of magnocellular and PNZ cells were classified as orthodromic excitatory (OD+) or inhibitory (OD-) after creating peri-stimulus time histograms (PSTHs). Twenty-six of 73 (35.6%) VP and OT cells and 16 of 42 (38.1%) PNZ cells were excited by optic nerve stimulation. PNZ cells displayed both short (for 7 cells 30 ms or less) and long (> 60 ms) latency responses. Most (6/7) short latency responses had a short duration but longer latency responses were longer. No magnocellular cells showed responses with both short latency and short duration. Short latency responses with a short duration probably reflect direct monosynaptic inputs whereas longer latency responses with longer duration may reflect complex inputs. Thus the retina projects to the PNZ and to the SON but the PNZ receives a stronger direct input. Such projections might provide a light-related input to SON cells and suggest a role for the PNZ in this input.

Peripheral T-cell lymphoma: aggressive disease with heterogeneous immunotypes.

Eleven patients with mature or peripheral T-cell lymphoma (PTL), other than mycosis fungoides, were identified using an extensive battery of T- and B-cell markers. Eight cases had a histologic diagnosis of either diffuse large cell or mixed lymphoma, three of small cell type. All cases had one or more "mature" T-antigens and an absence of B- and immature T-antigens. Assessment of T-antigens included E-rosettes (Er), anti-Leu 1-7 and Tdt. The authors delineated striking heterogeneity of T-antigen expression: 9 different immunotypes in 11 cases. Subset T-antigen assessment indicated T-helper neoplastic cells in five cases and T-suppressor in two. The remaining four had universal T-antigens alone. Seven cases appeared to have "novel" T-phenotypes not corresponding to normal T-ontogeny phenotypes. Novel or idiosyncratic phenotypes may be a key characteristic of PTL. Since no single T-antigen, including Er and Er receptor (Leu-5), was expressed in all cases, a battery of monoclonal antibodies is necessary to detect PTL. Clinically, the authors found PTL unexpectedly aggressive, despite mature immunotype. Most patients were elderly (median age 69); all had extranodal disease with cutaneous involvement (six cases) most frequent. Responses to chemotherapy frequently proved transient, with median survival of nine months. A fulminant course was noted even with localized presentation. Clinical outcome suggests PTL requires new therapeutic strategies.