Ramon Farré

Automatic control of tracheal tube cuff pressure in ventilated patients in semirecumbent position: A randomized trial*

Objective:The aspiration of subglottic secretions colonized by bacteria pooled around the tracheal tube cuff due to inadvertent deflation (<20 cm H2O) of the cuff plays a relevant role in the pathogenesis of ventilator-associated pneumonia. We assessed the efficacy of an automatic, validated device for the continuous regulation of tracheal tube cuff pressure in preventing ventilator-associated pneumonia. Design:Prospective randomized controlled trial. Setting:Respiratory intensive care unit and general medical intensive care unit. Patients:One hundred and forty-two mechanically ventilated patients (age, 64 ± 17 yrs; Acute Physiology and Chronic Health Evaluation II score, 18 ± 6) without pneumonia or aspiration at admission. Interventions:Within 24 hrs of intubation, patients were randomly allocated to undergo continuous regulation of the cuff pressure with the automatic device (n = 73) or routine care of the cuff pressure (control group, n = 69). Patients remained in a semirecumbent position in bed. Measurements and Main Results:The primary end point variable was the incidence of ventilator-associated pneumonia. Main causes for intubation were decreased consciousness (43, 30%) and exacerbation of chronic respiratory diseases (38, 27%). Cuff pressure <20 cm H2O was more frequently observed in the control than the automatic group (45.3 vs. 0.7% determinations, p < .001). However, the rate of ventilator-associated pneumonia with clinical criteria (16, 22% vs. 20, 29%) and microbiological confirmation (11, 15% vs. 10, 15%), the distribution of early and late onset, the causative microorganisms, and intensive care unit (20, 27% vs. 16, 23%) and hospital mortality (30, 41% vs. 23, 33%) were similar for the automatic and control groups, respectively. Conclusions:Cuff pressure is better controlled with the automatic device. However, it did not result in additional benefits to the semirecumbent position in preventing ventilator-associated pneumonia.

Micropatterning of single endothelial cell shape reveals a tight coupling between nuclear volume in G1 and proliferation.

Shape-dependent local differentials in cell proliferation are considered to be a major driving mechanism of structuring processes in vivo, such as embryogenesis, wound healing, and angiogenesis. However, the specific biophysical signaling by which changes in cell shape contribute to cell cycle regulation remains poorly understood. Here, we describe our study of the roles of nuclear volume and cytoskeletal mechanics in mediating shape control of proliferation in single endothelial cells. Micropatterned adhesive islands were used to independently control cell spreading and elongation. We show that, irrespective of elongation, nuclear volume and apparent chromatin decondensation of cells in G1 systematically increased with cell spreading and highly correlated with DNA synthesis (percent of cells in the S phase). In contrast, cell elongation dramatically affected the organization of the actin cytoskeleton, markedly reduced both cytoskeletal stiffness (measured dorsally with atomic force microscopy) and contractility (measured ventrally with traction microscopy), and increased mechanical anisotropy, without affecting either DNA synthesis or nuclear volume. Our results reveal that the nuclear volume in G1 is predictive of the proliferative status of single endothelial cells within a population, whereas cell stiffness and contractility are not. These findings show that the effects of cell mechanics in shape control of proliferation are far more complex than a linear or straightforward relationship. Our data are consistent with a mechanism by which spreading of cells in G1 partially enhances proliferation by inducing nuclear swelling and decreasing chromatin condensation, thereby rendering DNA more accessible to the replication machinery.

Intermittent hypoxia enhances cancer progression in a mouse model of sleep apnoea

To the Editors: Obstructive sleep apnoea (OSA) is a very prevalent syndrome that induces or aggravates cardiovascular, metabolic and neurocognitive disorders. Among the various challenges imposed on a patient by OSA as a consequence of apnoeas (sleep disruption, increased inspiratory efforts and recurrent hypoxaemia), intermittent hypoxia plays a major role in the pathophysiology of this sleep breathing disorder. It has been well established that hypoxia plays an important role in regulating the various stages of tumour formation and progression [1]. Accordingly, the aim of the experimental study reported here was to test the hypothesis that high-rate intermittent hypoxia with a time course similar to that found in OSA (one or more hypoxic event per minute) enhances tumour growth. To avoid the interaction of any comorbidity, this investigation was carried out in a well-controlled animal model where the main variable under study was intermittent hypoxia. This study, which was approved by the Ethical Committee for Animal Research of the University of Barcelona (Barcelona, Spain), was conducted in 15 pathogen-free male C57BL/6J mice (25–30 g) using a conventional murine melanoma model consisting of tumour induction by subcutaneous injection of 106 B16F10 melanoma cells (ATCC-CRL-6475; American Type Culture Collection, Manassas, VA, USA) in the left flank region of the mouse [2]. This is a widely used cancer model in experimental research [3, 4], which has a response to hypoxia that is representative of a variety of cancer types …

Automatic regulation of the cuff pressure in endotracheally- intubated patients

To avoid tracheal wall damage or inadvertent falls of the endotracheal tube cuff pressure (Pcuff) in intubated and mechanically-ventilated patients, the authors devised a simple procedure for automatic and continuous regulation of Pcuff. The procedure, only requiring a simple aquarium air pump and conventional tubing, was first tested at the bench when applied to an intubated and ventilated lung model, including an artificial trachea with an externally-variable section. The clinical performance of the procedure was tested in eight intubated patients, in whom the endotracheal tube cuff was connected to the designed Pcuff regulator during 24 h. The bench test showed that the procedure was able to maintain Pcuff constant, regardless of the changes imposed in the tracheal section. It was also effective in maintaining Pcuff during routine mechanical ventilation. Actual Pcuff recorded over the 24-h period always coincided with the target value within ±2 cmH2O in all the patients. The procedure devised to maintain endotracheal tube cuff pressure is readily implemented, cheap, easy to operate and can be used regardless of the specific ventilator or tube used. Routine implementation of this procedure may be useful for protecting the trachea from tissue damage and for reducing the risk of ventilator-associated pneumonia.

Intermittent Hypoxia-induced Changes in Tumor-associated Macrophages and Tumor Malignancy in a Mouse Model of Sleep Apnea

RATIONALE An increased cancer aggressiveness and mortality have been recently reported among patients with obstructive sleep apnea (OSA). Intermittent hypoxia (IH), a hallmark of OSA, enhances melanoma growth and metastasis in mice. OBJECTIVES To assess whether OSA-related adverse cancer outcomes occur via IH-induced changes in host immune responses, namely tumor-associated macrophages (TAMs). MEASUREMENTS AND MAIN RESULTS Lung epithelial TC1 cell tumors were 84% greater in mice subjected to IH for 28 days compared with room air (RA). In addition, TAMs in IH-exposed tumors exhibited reductions in M1 polarity with a shift toward M2 protumoral phenotype. Although TAMs from tumors harvested from RA-exposed mice increased TC1 migration and extravasation, TAMs from IH-exposed mice markedly enhanced such effects and also promoted proliferative rates and invasiveness of TC1 cells. Proliferative rates of melanoma (B16F10) and TC1 cells exposed to IH either in single culture or in coculture with macrophages (RAW 264.7) increased only when RAW 264.7 macrophages were concurrently present. CONCLUSIONS Our findings support the notion that IH-induced alterations in TAMs participate in the adverse cancer outcomes reported in OSA.

Electroencephalographic slowing heralds mild cognitive impairment in idiopathic REM sleep behavior disorder.

OBJECTIVE Patients with idiopathic rapid eye movement (REM) sleep behavior disorder (IRBD) may show electroencephalographic (EEG) slowing reflecting cortical dysfunction and are at risk for developing neurological conditions characterized by cognitive dysfunction including mild cognitive impairment (MCI), dementia with Lewy bodies and Parkinsons disease with associated dementia. We hypothesized that those IRBD patients who later developed MCI had pronounced cortical EEG slowing at presentation. METHODS Power EEG spectral analysis was blindly quantified from the polysomnographic studies of 23 IRBD patients without cognitive complaints and 10 healthy controls without RBD. After a mean clinical follow-up of 2.40+/-1.55 years, 10 patients developed MCI (RBD+MCI) and the remaining 13 remained idiopathic. RESULTS Patients with RBD+MCI had marked EEG slowing (increased delta and theta activity) in central and occipital regions during wakefulness and REM sleep, particularly in the right hemisphere, when compared with controls and, to a lesser extent, with IRBD subjects who remained idiopathic. The EEG spectral pattern of the RBD+MCI group was similar to that seen in patients with dementia with Lewy bodies and Parkinsons disease associated with dementia. CONCLUSION Our findings suggest that the presence of marked EEG slowing on spectral analysis might be indicative of the short-term development of MCI in patients initially diagnosed with IRBD.

Nasal prongs in the detection of sleep-related disordered breathing in the sleep apnoea/hypopnoea syndrome

Conventional systems to monitor oronasal flow in sleep studies have traditionally relied on a thermistor signal. Our study was designed to verify whether nasal prongs (NP) connected to a pressure transducer could improve respiratory events detection in patients with sleep apnoea/hypopnoea syndrome (SAHS) compared to traditional systems. Sleep episodes from a 2 h conventional polysomnographic record plus NP signal obtained at random from eight patients (age: mean(+/-SD) 53(+/-12) yrs; body mass index (BMI): 29(+/-6) kg x m(-2); apnoea/hypopnoea index (AHI): 27(+/-20) events x h(-1)) were identified and used for analysis. An abnormal change in the pattern of any of the respiratory or neurological variables occurring during the observation period was defined as an episode. Each episode was registered and scored with concomitant scoring of the remaining variables. According to the episode definition three different profiles were established: 1) periods of reduction of ventilation in either variable without an arousal or cyclical desaturation, named nonpathological episode (NPE); 2) an idiopathic or nonrespiratory arousal (IA); and 3) a true respiratory event (TRE) defined as reduction or absence of flow demonstrated by either thermistor, thoraco-abdominal bands or NP accompanied by cyclical desaturation and/or arousal. For each TRE, its detection by thermistor, thoraco-abdominal bands or NP was established. A total of 877 sleep episodes were observed (42 NPE, 30 IA and 805 TRE). When compared to single or combined thermistor and bands approach, NP had the highest respiratory events detection rate, 779 (96.8%) versus 673 events (83.6%), respectively. Detection of respiratory-related arousals was also improved by NP and only 3% could account for mouth breathing respiration. It is concluded that nasal prongs improve the detection of respiratory events in patients with sleep respiratory disorders.

Recurrent obstructive apneas trigger early systemic inflammation in a rat model of sleep apnea.

Obstructive sleep apnea (OSA) is associated with vascular disorders possibly due to systemic inflammation. To determine whether repeated episodes of OSA in a rat model lead to endothelial cell activation and systemic leukocyte recruitment in the microcirculation. Three experimental groups (apnea, sham and naive) were studied. The apnea group was instrumented and subjected to repeated obstruction for 3h (rate 60/h, length 5s) using a special device. The sham group was only instrumented and the naive group was used as a control. Leukocyte-endothelial cell interactions (intravital microscopy) and expression of P-selectin (immunohistochemistry) were determined in colonic venules. The apnea group induced a significant increase in the flux of leukocytes rolling, number of rolling leukocytes and number of adherent leukocytes when compared with the sham or naive groups. P-selectin was up-regulated only in the apnea group. This experimental model of recurrent obstruction demonstrates rapid endothelial cell activation, suggesting the onset of an inflammatory response.

Noninvasive monitoring of respiratory mechanics during sleep

The sleep apnoea–hypopnoea syndrome is characterised by recurrent obstructions of the upper airway, resulting in sleep disruption and arterial oxygen desaturations. Noninvasive assessment of respiratory mechanics during sleep is helpful in facilitating the diagnosis and treatment of patients with sleep apnoea–hypopnoea syndrome. This series summarises the different tools that are currently available to noninvasively assess respiratory mechanics during sleep breathing disturbances. These techniques are classified according to the main variable monitored: ventilation, breathing effort or airway obstruction. Changes in patient ventilation are assessed by recording flow or volume signals by means of pneumotachographs, thermistors or thermocouples, nasal prongs or thoraco-abdominal bands. Common tools to noninvasively assess breathing efforts are the thoraco-abdominal bands and the pulse transit time technique. Upper airway obstruction is noninvasively characterised by its upstream resistance and its critical pressure or by means of the forced oscillation technique. Given the technical and practical limitations of each technique, combining different tools improves the reliability and robustness of patient assessment during sleep.

Tissue Oxygenation in Brain, Muscle, and Fat in a Rat Model of Sleep Apnea: Differential Effect of Obstructive Apneas and Intermittent Hypoxia

STUDY OBJECTIVES To test the hypotheses that the dynamic changes in brain oxygen partial pressure (PtO(2)) in response to obstructive apneas or to intermittent hypoxia differ from those in other organs and that the changes in brain PtO(2) in response to obstructive apneas is a source of oxidative stress. DESIGN Prospective controlled animal study. SETTING University laboratory. PARTICIPANTS 98 Sprague-Dawley rats. INTERVENTIONS Cerebral cortex, skeletal muscle, or visceral fat tissues were exposed in anesthetized animals subjected to either obstructive apneas or intermittent hypoxia (apneic and hypoxic events of 15 s each and 60 events/h) for 1 h. MEASUREMENTS AND RESULTS Arterial oxygen saturation (SpO(2)) presented a stable pattern, with similar desaturations during both stimuli. The PtO(2) was measured by a microelectrode. During obstructive apneas, a fast increase in cerebral PtO(2) was observed (38.2 ± 3.4 vs. 54.8 ± 5.9 mm Hg) but not in the rest of tissues. This particular cerebral response was not found during intermittent hypoxia. The cerebral content of reduced glutathione was decreased after obstructive apneas (46.2% ± 15.2%) compared to controls (100.0% ± 14.7%), but not after intermittent hypoxia. This antioxidant consumption after obstructive apneas was accompanied by increased cerebral lipid peroxidation under this condition. No changes were observed for these markers in the other tissues. CONCLUSIONS These results suggest that cerebral cortex could be protected in some way from hypoxic periods caused by obstructive apneas. The increased cerebral PtO(2) during obstructive apneas may, however, cause harmful effects (oxidative stress). The obstructive apnea model appears to be more adequate than the intermittent hypoxia model for studying brain changes associated with OSA.