Near-fatal mucormycosis post-double lung transplant presenting as uncontrolled upper gastrointestinal haemorrhage.

Invasive fungal infections in immunosuppressed transplant patients are associated with significant morbidity and mortality. We present a case of splenic mucormycosis post-double lung transplant, presenting as uncontrolled near-fatal upper gastrointestinal haemorrhage, to remind clinicians of the need to consider pre-transplant invasive fungal infection risk factors if an unexpected fungal infection arises in the post-transplant period. This case also highlights the valuable contribution of molecular technology for fungal identification but also the need for clinical correlation.

Mechanisms of the deep, slow-wave, sleep-related increase of upper airway muscle tone in healthy humans.

Upper airway muscle activity is reportedly elevated during slow-wave sleep (SWS) when compared with lighter sleep stages. To uncover the possible mechanisms underlying this elevation, we explored the correlation between different indices of central and reflex inspiratory drive, such as the changes in airway pressure and end-expiratory CO2 and the changes in the genioglossus (GG) and tensor palatini (TP) muscle activity accompanying transitions from the lighter N2 to the deeper N3 stage of non-rapid eye movement (NREM) sleep in healthy young adult men. Forty-six GG and 38 TP continuous electromyographic recordings were obtained from 16 men [age: 20 ± 2.5 (SD) yr; body mass index: 22.5 ± 1.8 kg/m2] during 32 transitions from NREM stages N2 to N3. GG but not TP activity increased following transition into N3 sleep, and the increase was positively correlated with more negative airway pressure, increased end-tidal CO2, increased peak inspiratory flow, and increased minute ventilation. None of these correlations was statistically significant for TP. Complementary GG and TP single motor unit analysis revealed a mild recruitment of GG units and derecruitment of TP units during the N2 to N3 transitions. These findings suggest that, in healthy individuals, the increased GG activity during SWS is driven primarily by reflex stimulation of airway mechanoreceptors and central chemoreceptors.NEW & NOTEWORTHY The characteristic increase in the activity of the upper airway dilator muscle genioglossus during slow-wave sleep (SWS) in young healthy individuals was found to be related to increased stimulation of airway mechanoreceptors and central chemoreceptors. No evidence was found for the presence of a central SWS-specific drive stimulating genioglossus activity in young healthy individuals. However, it remains to be determined whether a central drive exists in obstructive sleep apnea patients.

Trazodone Effects on Obstructive Sleep Apnea and Non-REM Arousal Threshold.

RATIONALE: A low respiratory arousal threshold is a physiological trait involved in obstructive sleep apnea (OSA) pathogenesis. Trazodone may increase arousal threshold without compromising upper airway muscles, which should improve OSA. OBJECTIVES: We aimed to examine how trazodone alters OSA severity and arousal threshold. We hypothesized that trazodone would increase the arousal threshold and improve the apnea/hypopnea index (AHI) in selected patients with OSA. METHODS: Subjects were studied on two separate nights in a randomized crossover design. Fifteen unselected subjects with OSA (AHI ≥ 10/h) underwent a standard polysomnogram plus an epiglottic catheter to measure the arousal threshold. Subjects were studied after receiving trazodone (100 mg) and placebo, with 1 week between conditions. The arousal threshold was calculated as the nadir pressure before electrocortical arousal from approximately 20 spontaneous respiratory events selected randomly. MEASUREMENTS AND MAIN RESULTS: Compared with placebo, trazodone resulted in a significant reduction in AHI (38.7 vs. 28.5 events/h, P = 0.041), without worsening oxygen saturation or respiratory event duration. Trazodone was not associated with a significant change in the non-REM arousal threshold (-20.3 vs. -19.3 cm H2O, P = 0.51) compared with placebo. In subgroup analysis, responders to trazodone spent less time in N1 sleep (20.1% placebo vs. 9.0% trazodone, P = 0.052) and had an accompanying reduction in arousal index, whereas nonresponders were not observed to have a change in sleep parameters. CONCLUSIONS: These findings suggest that trazodone could be effective therapy for patients with OSA without worsening hypoxemia. Future studies should focus on underlying mechanisms and combination therapies to eliminate OSA. Clinical trial registered with www.clinicaltrials.gov (NCT 01817907).

Clinical predictors of the respiratory arousal threshold in patients with obstructive sleep apnea.

RATIONALE: A low respiratory arousal threshold (ArTH) is one of several traits involved in obstructive sleep apnea pathogenesis and may be a therapeutic target; however, there is no simple way to identify patients without invasive measurements. OBJECTIVES: To determine the physiologic determinates of the ArTH and develop a clinical tool that can identify patients with low ArTH. METHODS: Anthropometric data were collected in 146 participants who underwent overnight polysomnography with an epiglottic catheter to measure the ArTH (nadir epiglottic pressure before arousal). The ArTH was measured from up to 20 non-REM and REM respiratory events selected randomly. Multiple linear regression was used to determine the independent predictors of the ArTH. Logistic regression was used to develop a clinical scoring system. MEASUREMENTS AND MAIN RESULTS: Nadir oxygen saturation as measured by pulse oximetry, apnea-hypopnea index, and the fraction of events that were hypopneas (Fhypopneas) were independent predictors of the ArTH (r(2) = 0.59; P < 0.001). Using this information, we used receiver operating characteristic analysis and logistic regression to develop a clinical score to predict a low ArTH, which allocated a score of 1 to each criterion that was satisfied: (apnea-hypopnea index, <30 events per hour) + (nadir oxygen saturation as measured by pulse oximetry >82.5%) + (Fhypopneas >58.3%). A score of 2 or above correctly predicted a low arousal threshold in 84.1% of participants with a sensitivity of 80.4% and a specificity of 88.0%, a finding that was confirmed using leave-one-out cross-validation analysis. CONCLUSIONS: Our results demonstrate that individuals with a low ArTH can be identified from standard, clinically available variables. This finding could facilitate larger interventional studies targeting the ArTH.

Physiological mechanisms of upper airway hypotonia during REM sleep.

STUDY OBJECTIVES: Rapid eye movement (REM)-induced hypotonia of the major upper airway dilating muscle (genioglossus) potentially contributes to the worsening of obstructive sleep apnea that occurs during this stage. No prior human single motor unit (SMU) study of genioglossus has examined this possibility to our knowledge. We hypothesized that genioglossus SMUs would reduce their activity during stable breathing in both tonic and phasic REM compared to stage N2 sleep. Further, we hypothesized that hypopneas occurring in REM would be associated with coincident reductions in genioglossus SMU activity. DESIGN: The activity of genioglossus SMUs was studied in (1) neighboring epochs of stage N2, and tonic and phasic REM; and (2) during hypopneas occurring in REM. SETTING: Sleep laboratory. PARTICIPANTS: 29 subjects (38 ± 13 y) (17 male). INTERVENTION: Natural sleep, including REM sleep and REM hypopneas. MEASUREMENT AND RESULTS: Subjects slept overnight with genioglossus fine-wire intramuscular electrodes and full polysomnography. Forty-two SMUs firing during one or more of stage N2, tonic REM, or phasic REM were sorted. Twenty inspiratory phasic (IP), 17 inspiratory tonic (IT), and five expiratory tonic (ET) SMUs were characterized. Fewer units were active during phasic REM (23) compared to tonic REM (30) and stage N2 (33). During phasic REM sleep, genioglossus IP and IT SMUs discharged at slower rates and for shorter durations than during stage N2. For example, the SMU peak frequency during phasic REM 5.7 ± 6.6 Hz (mean ± standard deviation) was less than both tonic REM 12.3 ± 9.7 Hz and stage N2 16.1 ± 10.0 Hz (P < 0.001). The peak firing frequencies of IP/IT SMUs decreased from the last breath before to the first breath of a REM hypopnea (11.8 ± 10.9 Hz versus 5.7 ± 9.4 Hz; P = 0.001). CONCLUSION: Genioglossus single motor unit activity is significantly reduced in REM sleep, particularly phasic REM. Single motor unit activity decreases abruptly at the onset of REM hypopneas.

Adult obstructive sleep apnoea.

Obstructive sleep apnoea is an increasingly common disorder of repeated upper airway collapse during sleep, leading to oxygen desaturation and disrupted sleep. Features include snoring, witnessed apnoeas, and sleepiness. Pathogenesis varies; predisposing factors include small upper airway lumen, unstable respiratory control, low arousal threshold, small lung volume, and dysfunctional upper airway dilator muscles. Risk factors include obesity, male sex, age, menopause, fluid retention, adenotonsillar hypertrophy, and smoking. Obstructive sleep apnoea causes sleepiness, road traffic accidents, and probably systemic hypertension. It has also been linked to myocardial infarction, congestive heart failure, stroke, and diabetes mellitus though not definitively. Continuous positive airway pressure is the treatment of choice, with adherence of 60-70%. Bi-level positive airway pressure or adaptive servo-ventilation can be used for patients who are intolerant to continuous positive airway pressure. Other treatments include dental devices, surgery, and weight loss.

A mechanism for upper airway stability during slow wave sleep.

STUDY OBJECTIVES: The severity of obstructive sleep apnea is diminished (sometimes markedly) during slow wave sleep (SWS). We sought to understand why SWS stabilizes the upper airway. Increased single motor unit (SMU) activity of the major upper airway dilating muscle (genioglossus) should improve upper airway stability. Therefore, we hypothesized that genioglossus SMUs would increase their activity during SWS in comparison with Stage N2 sleep. DESIGN: The activity of genioglossus SMUs was studied on both sides of the transition between Stage N2 sleep and SWS. SETTING: Sleep laboratory. PARTICIPANTS: Twenty-nine subjects (age 38 ± 13 yr, 17 males) were studied. INTERVENTION: SWS. MEASUREMENT AND RESULTS: Subjects slept overnight with fine-wire electrodes in their genioglossus muscles and with full polysomnographic and end tidal carbon dioxide monitors. Fifteen inspiratory phasic (IP) and 11 inspiratory tonic (IT) units were identified from seven subjects and these units exhibited significantly increased inspiratory discharge frequencies during SWS compared with Stage N2 sleep. The peak discharge frequency of the inspiratory units (IP and IT) was 22.7 ± 4.1 Hz in SWS versus 20.3 ± 4.5 Hz in Stage N2 (P < 0.001). The IP units also fired for a longer duration (expressed as a percentage of inspiratory time) during SWS (104.6 ± 39.5 %TI) versus Stage N2 sleep (82.6 ± 39.5 %TI, P < 0.001). The IT units fired faster during expiration in SWS (14.2 ± 1.8 Hz) versus Stage N2 sleep (12.6 ± 3.1 Hz, P = 0.035). There was minimal recruitment or derecruitment of units between SWS and Stage N2 sleep. CONCLUSION: Increased genioglossus SMU activity likely makes the airway more stable and resistant to collapse throughout the respiratory cycle during SWS.

Sleep quality in chronic obstructive pulmonary disease.

BACKGROUND AND OBJECTIVE: Previous reports have shown that patients with chronic obstructive pulmonary disease (COPD) sleep poorly, but the underlying basis remains speculative. The aim of this retrospective study was to determine potential predictors of poor sleep quality in COPD patients. METHODS: This is a secondary analysis of two previously published trials investigating the impact of long-acting bronchodilators on nocturnal oxygen saturation in moderate to severe COPD patients. One hundred and six patients with established COPD were studied. Each patient underwent overnight polysomnography studies in a dedicated university-affiliated sleep laboratory. Epworth Sleepiness Scores, spirometry and daytime arterial oxygen tension (PaO(2)) were also recorded. Univariate and multivariate analysis sought independent predictors of sleep quality from baseline demographic, spirometry and oximetry values. RESULTS: Patients' age was 66.4 ± 7.3 years (mean ± standard deviation), forced expiratory volume in 1 s (FEV(1)) 33.4 ± 12.9% predicted and daytime PaO(2) 64 ± 7.5 mm Hg. In comparison with historical normative populations, the cohort demonstrated impaired sleep quality. Sleep efficiency was 66 ± 17% and sleep stage analysis revealed altered architecture with diminished periods of rapid eye movement sleep (12.7 ± 8.3%). In multivariate analysis, daytime PaO(2) correlated independently with sleep efficiency (P = 0.041), whereas FEV(1) positively correlated with arousal index, and age correlated negatively with rapid eye movement sleep duration. CONCLUSIONS: Sleep quality is poor in patients with severe COPD compared with normative populations of similar age, and daytime hypoxaemia is independently associated with impaired sleep efficiency.

Adaptive servoventilation for treatment of sleep-disordered breathing in heart failure: a systematic review and meta-analysis.

BACKGROUND: Adaptive servoventilation (ASV) has demonstrated efficacy in treating sleep-disordered breathing (SDB) in patients with heart failure (HF), but large randomized trials are lacking. We, therefore, sought to perform a systematic review and meta-analysis of existing data. METHODS: A systematic search of the PubMed database was undertaken in March 2012. Publications were independently assessed by two investigators to identify studies of ≥ 1-week duration that compared ASV to a control condition (ie, subtherapeutic ASV, continuous or bilevel pressure ventilation, oxygen therapy, or no treatment) in adult patients with SDB and HF. Mean, variability,and sample size data were extracted independently for the following outcomes: apneahypopnea index (AHI), left ventricular ejection fraction (LVEF), quality of life (SF-36 Health Survey; Medical Outcomes Trust), 6-min walk distance, peak oxygen consumption ( VO 2 ) % predicted, and ventilatory equivalent ratio for CO 2 ( VE / Vco 2 ) slope measured during exercise. Random effects meta-analysis models were applied. RESULTS: Fourteen studies were identified (N = 538). Comparing ASV to control conditions, the weighted mean difference in AHI ( -14.64 events/h; 95% CI, -21.03 to - 8.25) and LVEF (0.40;95% CI, 0.08-0.71) both significantly favored ASV. ASV also improved the 6-min walk distance,but not peak O 2 % predicted, VE / VCO 2 slope, or quality of life, compared with control conditions. CONCLUSIONS: In patients with HF and SDB, ASV was more effective than control conditions in reducing the AHI and improving cardiac function and exercise capacity. These data provide a compelling rationale for large-scale randomized controlled trials to assess the clinical impact of ASV on hard outcomes in these patients.

Neurogenic changes in the upper airway of patients with obstructive sleep apnea.

RATIONALE: Controversy persists regarding the presence and importance of hypoglossal nerve dysfunction in obstructive sleep apnea (OSA). OBJECTIVES: We assessed quantitative parameters related to motor unit potential (MUP) morphology derived from electromyographic (EMG) signals in patients with OSA versus control subjects and hypothesized that signs of neurogenic remodeling would be present in the patients with OSA. METHODS: Participants underwent diagnostic sleep studies to obtain apnea-hypopnea indices. Muscle activity was detected with 50-mm concentric needle electrodes. The concentric needle was positioned at more than 10 independent sites per subject, after the local anatomy of the upper airway musculature was examined by ultrasonography. All activity was quantified with subjects awake, during supine eupneic breathing while wearing a nasal mask connected to a pneumotachograph. Genioglossus EMG signals were analyzed offline by automated software (DQEMG), which extracted motor unit potential trains (MUPTs) contributed by individual motor units from the composite EMG signals. Quantitative measurements of MUP templates, including duration, peak-to-peak amplitude, area, area-to-amplitude ratio, and size index, were compared between the untreated patients with OSA and healthy control subjects. MEASUREMENTS AND MAIN RESULTS: A total of 1,655 MUPTs from patients with OSA (n = 17; AHI, 55 ± 6/h) and control subjects (n = 14; AHI, 4 ± 1/h) were extracted from the genioglossus muscle EMG signals. MUP peak-to-peak amplitudes in the patients with OSA were not different compared with the control subjects (397.5 ± 9.0 vs. 382.5 ± 10.0 µV). However, the MUPs of the patients with OSA were longer in duration (11.5 ± 0.1 vs. 10.3 ± 0.1 ms; P < 0.001) and had a larger size index (4.09 ± 0.02 vs. 3.92 ± 0.02; P < 0.001) compared with control subjects. CONCLUSIONS: These results confirm and quantify the extent and existence of structural neural remodeling in OSA.

Towards a genioglossus surface EMG model of obstructive sleep apnea.

The behaviour and activity of the genioglossus muscle during sleep is of considerable interest to investigators of obstructive sleep apnea syndrome. Therefore, we contribute an model of genioglossus EMG activity during breathing, based on recent physiological findings. We present the modelling techniques and simulation results. The model incorporates new data on fibre type, motor unit type and motor unit firing characteristics. Although we report its use for modelling genioglossus surface EMG, this model can be used to simulate both genioglossus surface and intramuscular EMGs of various electrode configurations. We also discuss the simulation results in the context of the limited experimental data available for surface genioglossus EMG in obstructive sleep apnea.