Diaphragm Morphology Assessed by Computed Tomography in Chronic Obstructive Pulmonary Disease.

Rationale: Chronic obstructive pulmonary disease (COPD) is associated with abnormal skeletal muscle morphology and function. Objectives: To test the hypothesis that in vivo diaphragm muscle morphology assessed by computed tomography (CT) imaging would be associated with COPD severity, exacerbations, health status, and exercise capacity. Methods: The COPD Morphometry Study is a cross-sectional study that enrolled a clinical sample of smokers with COPD. Spirometry was performed and COPD severity was defined according to guidelines. Three-dimensional left hemidiaphragm morphology was segmented from contiguous axial CT images acquired at maximal inspiration, yielding quantitative measures of diaphragm CT density in Hounsfield units, dome height, and muscle volume. Exacerbations prompting pharmacotherapy or hospitalization in the preceding 12 months and St. George's Respiratory Questionnaire for COPD were assessed. Incremental symptom-limited cycle ergometry quantified peak oxygen uptake ([Formula: see text]o2Peak). Associations were adjusted for age, sex, body height, body mass index, and smoking status. Results: Among 65 smokers with COPD (75% male; [mean ± standard deviation (SD)] 56 ± 26 pack-years; forced expiratory volume in 1 second [FEV1] percentage predicted 55 ± 23%), mean diaphragm CT density was 3.1 ± 10 Hounsfield units, dome height was 5.2 ± 1.3 cm, and muscle volume was 57 ± 24 cm3. A 1-SD decrement in the diaphragm CT density was associated with 8.3% lower FEV1, 3.27-fold higher odds of exacerbation history, 9.7-point higher score on the St. George's Respiratory Questionnaire for COPD, and 2.5 ml/kg/min lower [Formula: see text]o2Peak. A 1-SD decrement in dome height was associated with 11% lower FEV1 and 1.3 ml/kg/min lower [Formula: see text]o2Peak. There were no associations with diaphragm volume observed. Conclusions: CT-assessed diaphragm morphology was associated with COPD severity, exacerbations, impaired health status, and exercise intolerance. The mechanisms and functional impact of lower diaphragm CT density merit investigation.

Dyspnea and surface inspiratory electromyograms in mechanically ventilated patients.

CONTEXT: Pressure support ventilation (PSV) must be tailored to the load capacity balance of the respiratory system. While "over assistance" generated hyperinflation and ineffective efforts, "under assistance" increased respiratory drive and causes dyspnea. Surface electromyograms (sEMGs) of extradiaphragmatic inspiratory muscles were responsive to respiratory loading/unloading. OBJECTIVES: To determine if sEMGs of extradiaphragmatic inspiratory muscles vary with PSV settings and relate to the degree of discomfort and the intensity of dyspnea in acutely ill patients. DESIGN: Pathophysiological study, prospective inclusions of 12 intubated adult patients. INTERVENTIONS: Two PSV levels (high and low) and two expiratory trigger (ET) levels (high and low). MEASUREMENTS: Surface electromyograms of the scalene, parasternal, and Alae Nasi muscles (peak, EMGmax; area under the curve, EMGAUC); dyspnea visual analogue scale (VAS); prevalence of ineffective triggering efforts. MAIN RESULTS: For the three recorded muscles, EMGmax and EMGAUC were significantly greater with low PS than high PS. The influence of ET was less important. A strong correlation was found between dyspnea and EMGmax. A significant inverse correlation was found between the prevalence of ineffective efforts and both dyspnea-VAS and EMGmin. CONCLUSIONS: Surface electromyograms of extradiaphragmatic inspiratory muscles provides a simple, reliable and non-invasive indicator of respiratory muscle loading/unloading in mechanically ventilated patients. Because this EMG activity is strongly correlated to the intensity of dyspnea, it could be used as a surrogate of respiratory sensations in mechanically ventilated patients, and might, therefore, provide a monitoring tool in patients in whom detection and quantification of dyspnea is complex if not impossible.

Repetitive magnetic stimulation of the phrenic nerves for diaphragm conditioning: a normative study of feasibility and optimal settings.

Electrical stimulation can enhance muscle function. We applied repetitive cervical magnetic phrenic stimulation (rCMS) to induce diaphragm contractions in 7 healthy subjects (800 ms trains; transdiaphragmatic pressure (Pdi) measurements; tolerance ratings). Each rCMS train produced a sustained diaphragm contraction. Sixty-five percent of the maximal available output at 15 Hz proved the best compromise between Pdi and discomfort with nonfatiguing contractions. rCMS appears feasible and should be investigated for diaphragm conditioning in appropriate clinical populations.

Mechanical ventilation-induced diaphragm disuse in humans triggers autophagy.

RATIONALE: Controlled mechanical ventilation (CMV) results in atrophy of the human diaphragm. The autophagy-lysosome pathway (ALP) contributes to skeletal muscle proteolysis, but its contribution to diaphragmatic protein degradation in mechanically ventilated patients is unknown. OBJECTIVES: To evaluate the autophagy pathway responses to CMV in the diaphragm and limb muscles of humans and to identify the roles of FOXO transcription factors in these responses. METHODS: Muscle biopsies were obtained from nine control subjects and nine brain-dead organ donors. Subjects were mechanically ventilated for 2 to 4 hours and 15 to 276 hours, respectively. Activation of the ubiquitin-proteasome system was detected by measuring mRNA expressions of Atrogin-1, MURF1, and protein expressions of UBC2, UBC4, and the α subunits of the 20S proteasome (MCP231). Activation of the ALP was detected by electron microscopy and by measuring the expressions of several autophagy-related genes. Total carbonyl content and HNE-protein adduct formation were measured to assess oxidative stress. Total AKT, phosphorylated and total FOXO1, and FOXO3A protein levels were also measured. MEASUREMENTS AND MAIN RESULTS: Prolonged CMV triggered activation of the ALP as measured by the appearance of autophagosomes in the diaphragm and increased expressions of autophagy-related genes, as compared with controls. Induction of autophagy was associated with increased protein oxidation and enhanced expression of the FOXO1 gene, but not the FOXO3A gene. CMV also triggered the inhibition of both AKT expression and FOXO1 phosphorylation. CONCLUSIONS: We propose that prolonged CMV causes diaphragm disuse, which, in turn, leads to activation of the ALP through oxidative stress and the induction of the FOXO1 transcription factor.

Neurally adjusted ventilatory assist increases respiratory variability and complexity in acute respiratory failure.

BACKGROUND: Neurally adjusted ventilatory assist (NAVA) is a partial ventilatory support mode where positive pressure is provided in relation to diaphragmatic electrical activity (EAdi). Central inspiratory activity is normally not monotonous, but it demonstrates short-term variability and complexity. The authors reasoned that NAVA should produce a more "natural" or variable breathing pattern than other modes. This study compared respiratory variability and complexity during pressure support ventilation (PSV) and NAVA. METHODS: Flow and EAdi were recorded during routine PSV (tidal volume approximately 6-8 ml/kg) and four NAVA levels (1-4 cm H2O/microVEAdi) in 12 intubated patients. Breath-by-breath variability of flow and EAdi-related variables was quantified by the coefficient of variation (CV) and autocorrelation analysis. Complexity of flow and EAdi was described using noise titration, largest Lyapunov exponent, Kolmogorov-Sinai entropy, and three-dimensional phase portraits. RESULTS: Switching from PSV to NAVA increased the CV and decreased the autocorrelation for most flow-related variables in a dose-dependent manner (P < 0.05, partial eta for the CV of mean inspiratory flow 0.642). The changes were less marked for EAdi. A positive noise limit was consistently found for flow and EAdi. Largest Lyapunov exponent and Kolmogorov-Sinai entropy for flow were greater during NAVA than PSV and increased with NAVA level (P < 0.05, partial eta 0.334 and 0.312, respectively). Largest Lyapunov exponent and Kolmogorov-Sinai entropy for EAdi were not influenced by ventilator mode. CONCLUSIONS: Compared with PSV, NAVA increases the breathing pattern variability and complexity of flow, whereas the complexity of EAdi is unchanged. Whether this improves clinical outcomes remains to be determined.

Effects of inspiratory loading on the chaotic dynamics of ventilatory flow in humans.

Human ventilation at rest exhibits complexity and chaos. The aim of this study was to determine whether suprapontine interferences with the automatic breathing control could contribute to ventilatory chaos. We conducted a post hoc analysis of a previous study performed in awake volunteers exhibiting cortical pre-motor potentials during inspiratory loading. In eight subjects, flow was recorded at rest, while breathing against inspiratory threshold loads (median 21.5 cm H(2)O) and resistive loads (50 cm H(2)Ol(-1)s(-1)) loads, and while inhaling 7% CO(2)-93% O(2). Chaos was identified through noise titration (noise limit, NL) and the sensitivity to initial conditions was assessed through the largest Lyapunov exponent (LLE). Breath-by-breath variability was evaluated using the coefficient of variation of several ventilatory variables. Chaos was consistently present in ventilatory flow recordings, but mechanical loading did not alter NL, LLE, or variability. In contrast, CO(2) altered chaos and reduced variability. In conclusion, inspiratory loading - and any resultant respiratory-related cortical activity - were not associated with changes in ventilatory chaos in this study, arguing against suprapontine contributions to ventilatory complexity.

Tracheal pressure regulated volume assist ventilation in acute respiratory failure.

PURPOSE: Proportional assist ventilation (PAV) uses volume assist (VAV) and flow assist ventilation (FAV) to reduce elastic and resistive effort, respectively. Proportional assist ventilation may be difficult to apply clinically, particularly due to FAV related considerations. It was hypothesized that regulating tracheal (Ptr) rather than airway opening pressure (Pao), to overcome endotracheal tube related resistive effort, during VAV would provide an effective alternative method of ventilation. We therefore compared the effects of Pao and Ptr regulated VAV on breathing pattern and inspiratory effort. METHODS: In seven intubated patients, flow, volume, Pao, Ptr, esophageal and transdiaphragmatic pressure were measured during VAV (0-80% respiratory system elastance) using Pao vs Ptr to regulate ventilator applied pressure. Breathing pattern and the pressure-time integral of the inspiratory muscles (integralP(mus) . dt) and diaphragm (integralP(di) . dt) were determined. RESULTS: Compared to spontaneous breathing, the respiratory rate to tidal volume ratio, or rapid shallow breathing index (RSBI), improved progressively with increasing VAV (130 +/- 64 vs 70 +/- 35, VAV 0 vs 80%; P < 0.05) while inspiratory effort fell (integralP(mus) . dt = 39.6 +/- 7.5 vs 28.5 +/- 7.2 cm H(2)O.sec.L(-1), integralP(di) . dt, = 35.4 +/- 7.8 vs 24.2 +/- 5.9 cm H(2)O.sec.L(-1), VAV 0 vs 80%; P < 0.05) due to a decrease in elastic related effort. At any given level of support, there was further reduction in RSBI, integralP(mus) . dt, and integralP(di) . dt (which averaged 23.6 +/- 2.7, 33.7 +/- 4.4, and 38.5 +/- 5.1%, respectively; P < 0.05) for Ptr compared to Pao regulated VAV due to a decrease in resistive effort. CONCLUSIONS: Tracheal pressure regulated VAV can be a simple and effective method of partial ventilatory support in acute respiratory failure. Further work will be needed to determine its efficacy and potential benefit relative to PAV and other modes of ventilation in routine clinical practice.

Incidence, risk factors and consequences of ICU delirium.

OBJECTIVE: Delirium in the critically ill is reported in 11-80% of patients. We estimated the incidence of delirium using a validated scale in a large cohort of ICU patients and determined the associated risk factors and outcomes. DESIGN AND SETTING: Prospective study in a 16-bed medical-surgical intensive care unit (ICU). PATIENTS: 820 consecutive patients admitted to ICU for more than 24 h. INTERVENTIONS: Tools used were: the Intensive Care Delirium Screening Checklist for delirium, Richmond Agitation and Sedation Scale for sedation, and Numerical Rating Scale for pain. Risk factors were evaluated with univariate and multivariate analysis, and factors influencing mortality were determined using Cox regression. RESULTS: Delirium occurred in 31.8% of 764 patients. Risk of delirium was independently associated with a history of hypertension (OR 1.88, 95% CI 1.3-2.6), alcoholism (2.03, 1.2-3.2), and severity of illness (1.25, 1.03-1.07 per 5-point increment in APACHE II score) but not with age or corticosteroid use. Sedatives and analgesics increased the risk of delirium when used to induce coma (OR 3.2, 95% CI 1.5-6.8), and not otherwise. Delirium was linked to longer ICU stay (11.5+/-11.5 vs. 4.4+/-3.9 days), longer hospital stay (18.2+/-15.7 vs. 13.2+/-19.4 days), higher ICU mortality (19.7% vs. 10.3%), and higher hospital mortality (26.7% vs. 21.4%). CONCLUSION: Delirium is associated with a history of hypertension and alcoholism, higher APACHE II score, and with clinical effects of sedative and analgesic drugs.

Contribution to structural intensity tool: application to the cancellation of ECG interference in diaphragmatic EMG.

This paper is concerned with the problem of localizing the typical features of a signal when it is observed with noise in order to align a set of curves. Structural intensity (SI) is a recent tool that computes the "density" of the location of the modulus maxima of a wavelet representation along various scales in order to identify singularities of an unknown signal. As a contribution to this novel approach we establish a modified SI using the Berkner transform which allows maxima linkage to insure accurate localization of singularities. An application to cancellation of ECG interference in diaphragmatic EMG is also proposed.

Olanzapine vs haloperidol: treating delirium in a critical care setting.

OBJECTIVE: To compare the safety and estimate the response profile of olanzapine, a second-generation antipsychotic, to haloperidol in the treatment of delirium in the critical care setting. DESIGN: Prospective randomized trial. SETTING: Tertiary care university affiliated critical care unit. PATIENTS: All admissions to a medical and surgical intensive care unit with a diagnosis of delirium. INTERVENTIONS: Patients were randomized to receive either enteral olanzapine or haloperidol. MEASUREMENTS: Patient's delirium severity and benzodiazepine use were monitored over 5 days after the diagnosis of delirium. MAIN RESULTS: Delirium Index decreased over time in both groups, as did the administered dose of benzodiazepines. Clinical improvement was similar in both treatment arms. No side effects were noted in the olanzapine group, whereas the use of haloperidol was associated with extrapyramidal side effects. CONCLUSIONS: Olanzapine is a safe alternative to haloperidol in delirious critical care patients, and may be of particular interest in patients in whom haloperidol is contraindicated.

Controlled mechanical ventilation leads to remodeling of the rat diaphragm.

Little is known about the structural response of the diaphragm to controlled mechanical ventilation. We examined effects of this intervention on muscle mass, myosin heavy chain isoforms, and contractile function in the rat diaphragm. Animals were mechanically ventilated for up to 4 days, and comparisons were made with normal control rats as well as spontaneously breathing animals anesthetized for the same duration as the mechanical ventilation group. The diaphragm-to-body weight ratio was significantly reduced in the mechanical ventilation group only. After mechanical ventilation, an increase in hybrid fibers coexpressing both type I (slow) and type II (fast) myosin isoforms was found within the diaphragm, which occurred at the expense of the pure type I fiber population. In contrast, the percentages of type I, type II, and hybrid fibers in the limb muscles (soleus and extensor digitorum longus) did not differ between experimental groups. The optimal length for force production, as well as maximal force-generating capacity of the diaphragm, was also significantly decreased in mechanically ventilated animals. We conclude that even short-term controlled mechanical ventilation produces significant remodeling and functional alterations of the diaphragm, which could impede efforts at discontinuing ventilatory support.

Mechanical ventilation protects against diaphragm injury in sepsis: interaction of oxidative and mechanical stresses.

Overproduction of nitric oxide (NO) with attendant oxidative and nitrosative stress has been implicated in sepsis-induced diaphragm dysfunction. Here we determined the impact of controlled mechanical ventilation (MV) on rat diaphragm sarcolemmal injury, inducible NO synthase (iNOS) expression, and oxidative stress during endotoxemia. At 4 h after injection of endotoxin, impaired sarcolemmal integrity and decreased force production by the diaphragm were observed in spontaneously breathing rats. The use of MV during endotoxemia largely eliminated sarcolemmal damage and significantly improved diaphragm force production. These benefits were not associated with alterations in either iNOS expression or protein carbonyls (marker of oxidation), which remained abnormally elevated in septic diaphragms despite MV. Therefore, we hypothesized that the protection afforded by MV was due to its ability to decrease the level of mechanical stress placed on the sarcolemma, because the latter could be hyperfragile in the setting of increased oxidative stress. Using an in vitro system to independently modulate oxidative and mechanical stresses, we confirmed that these two factors act together in a synergistic fashion to favor sarcolemmal injury. Accordingly, our data suggest that MV protects the diaphragm during sepsis by abrogating an injurious interaction between oxidative and biomechanical stresses imposed on the sarcolemma.