Exposure to obinutuzumab does not affect outcomes of SARS-CoV-2 infection in vaccinated patients with newly diagnosed advanced-stage follicular lymphoma.

URBAN is a multicentric, ambispective study evaluating the effectiveness and safety of obinutuzumab-based immuno-chemotherapy and maintenance in patients with untreated advanced follicular lymphoma (FL). The study began before the COVID-19 emergency declaration in Italy. It is currently ongoing for follow-up, and the enrolment timeline encompassed different stages of the pandemic, various vaccination roll-out phases and prevalence of SARS-CoV-2 variants. Outcomes of interest of the present sub-analysis included SARS-CoV-2 infection rates and COVID-19-related hospitalizations/deaths. At data cut-off, 86 (28.8%) and 213 patients (71.2%) were treated before and during/after the COVID-19 outbreak respectively; 294 (98.3%) completed the induction, 31 (10.4%) completed maintenance and 170 (56.9%) were still on maintenance. Overall, 245 patients (81.9%) received at least one SARS-CoV-2 vaccine dose: 13.5%, 31.4% and 55.1% received one, two and three doses respectively. We observed a substantial decrease in COVID-19-related mortality rates in pre- versus post-vaccination phases, along with a reduction in COVID-19-related outcomes due to the shift from alpha/delta to omicron variant predominance. No differences emerged between patients given maintenance or not, although the schedule was modified in 65% of cases. To our knowledge, URBAN represents the largest dataset of COVID-19-related outcomes in FL patients extensively exposed to obinutuzumab. ClinicalTrials.gov identifier: NCT04034056.

Skip pattern approach toward the early access of innovative anticancer drugs.

BACKGROUND: With the rapid development of innovative anticancer treatments, the optimization of tools able to accelerate the access of new drugs to the market by the regulatory authority is a major issue. The aim of the project was to propose a reliable methodological pathway for the assessment of clinical value of new therapeutic innovative options, to objectively identify drugs which deserve early access (EA) priority for solid and possibly in other cancer scenarios, such as the hematological ones. MATERIALS AND METHODS: After a comprehensive review of the European Public Assessment Report of 21 drugs, to which innovation had previously been attributed by the Italian Medicines Agency (Agenzia Italiana del Farmaco, AIFA), an expert panel formulated an algorithm for the balanced use of three parameters: Unmet Medical Need (UMN) according to AIFA criteria, Added Benefit (AB) according to the European Society for Medical Oncology's Magnitude of Clinical Benefit Scale (ESMO-MCBS) criteria and Quality of Evidence (QE) assessed by the Grades of Recommendation Assessment, Development and Evaluation (GRADE) method. By sequentially combining the above indicators, a final priority status (i.e. EA or not) was obtained using the skip pattern approach (SPA). RESULTS: By applying the SPA to the non-curative setting in solid cancers, the EA status was obtained by 5 out of 14 investigated drugs (36%); by enhancing the role of some categories of the UMN, additional 4 drugs, for a total of 9 (64%), reached the EA status: 2 and 3 drugs were excluded for not achieving an adequate score according to AB and QE criteria, respectively. For hematology cancer, only the UMN criteria were found to be adequate. CONCLUSIONS: The use of this model may represent a reliable tool for assessment available to the various stakeholders involved in the EA process and may help regulatory agencies in a more comprehensive and objective definition of new treatments' value in these contexts. Its generalizability in other national contexts needs further evaluation.

Outcome in patients with diffuse large B-cell lymphoma who relapse after autologous stem cell transplantation and receive active therapy. A retrospective analysis of the Lymphoma Working Party of the European Society for Blood and Marrow Transplantation (EBMT).

Autologous hematopoietic stem cell transplantation (auto-HSCT) is the standard of care for patients with diffuse large B-cell lymphoma (DLBCL) who relapse/progress after first line chemoimmunotherapy. Long-term outcome of those who relapse after transplant is poor. We present the results of a retrospective study of 256 adult patients reported to the EBMT registry with DLBCL who relapsed after auto-HSCT performed between 2003 and 2013, and who received active salvage strategies. One hundred and fifty-four (60%) were male; median age was 53 years. Median time to relapse was 7 months, 65% relapsed during the first year. Overall response rate after salvage therapy was 46%. Median follow-up after first salvage therapy was 40 months (IQR 23-63 months). Overall survival (OS) at 3 years was 27% (95% CI 22-33). OS at 3 years of patients relapsing longer than 1 year after auto-HSCT was 41% (95% CI 31-53) compared with 20% (95% CI 14-24) in those who relapsed in less than 1 year. Eighty-two patients (32%) had a second HSCT, an allogeneic HSCT (allo-HSCT) in 69 cases, at a median time of 6.5 months after relapse. OS at 3 years after allo-HSCT was 36% (95% CI 25-51). In conclusion, the prognosis of patients with DLBCL that relapse after auto-HSCT is dismal. Patients who relapse in less than 1 year remain an unmet need, and should be considered for CAR T cell therapy or clinical trials. Patients who relapse after 1 year can be rescued with salvage therapies and a second HSCT. These results provide a benchmark to compare data of new prospective studies.

Breast cancer electron intraoperative radiotherapy: assessment of preoperative selection factors from a retrospective analysis of 758 patients and review of literature.

PURPOSE: To report our experience with full-dose 21 Gy IORT in early breast cancer patients after breast-conserving surgery to define most important selection factors. METHODS: Seven hundred and fifty eight patients, subjected to conserving surgery and IORT, were retrospectively analyzed evaluating most important clinical outcomes. RESULTS: Median follow up was 5.2 years. Results from Cox analyses defined 2 groups of patients, "suitable" (age > 50 years, non lobular histology, tumour size ≤ 2 cm, pN0 or pNmic, ki67 ≤ 20%, non triple negative receptor status and G1-G2) and "unsuitable" for IORT, with a higher rate of breast related events moving from "suitable" to "unsuitable" group. The 5 year rate of IBR is 1.8% in suitable group with significant differences versus unsuitable (1.8 vs. 11.6%, p < 0.005). Same differences between two groups were evidenced in true local relapse (0.6 vs. 6.9%, p < 0.005) and in new ipsilateral BC (1.1 vs. 4.7%, p < 0.015). CONCLUSIONS: In our current practice we consider the following preoperative factors to select patients suitable for IORT: age > 50 years, absence of lobular histology, tumor size ≤ 2 cm, pN0 or pNmic, according to APBI consensus statement, including also ki67 ≤ 20%, non triple negative receptor status and G1-G2.

Effects of chronic administration of ß-blockers on airway responsiveness in a murine model of heart failure.

Lung function abnormalities, both at rest and during exercise, are frequently observed in patients with chronic heart failure (HF), also in absence of respiratory disease. It has been documented that, in HF, chronic adrenergic stimulation down-regulates ß-adrenoceptors (ß-ARs) and modifies airway relaxant responses. This study was designed to investigate in an animal model of HF whether a treatment with a ß-AR blocker, metoprolol, could modify the altered airway hyperresponsiveness. In rats, randomly assigned to 3 experimental groups sham-operated rats (SH), rats with HF induced by left anterior descending coronaric occlusion (HF n = 10), and rats treated with metoprolol 100 mg/kg/die (MET = 10), HF was evaluated after 10 weeks and resulted in increases in plasma norepinephrine and epinephrine and left ventricular end diastolic pressure. ß2-ARs and G-protein-ßAR2-kinase (GRK2) mRNA levels were determined by real time reverse transcriptase PCR. Carbachol-precontracted isolated tracheal rings were used to functionally assess airway smooth muscle relaxation. In pulmonary tissues, ß2-AR mRNA level was significantly decreased in HF groups (-48.73 ± 5.18%, P < 0.01); in the same groups the GRK2 mRNA-levels were significantly enhanced (+222.50 ± 6.13%, P < 0.001); in lung deriving from MET groups the levels of mRNA were significantly increased (+339.86 ± 11.26%, P < 0.001), while the GRK2 mRNA-levels unchanged (-59.02 ± 3.97%, P < 0.001), when compared to SH groups. Relaxation of tracheal strips in response to salbutamol was significantly reduced in HF groups; in tracheal rings, deriving from MET groups, the relaxant effects of salbutamol were significantly enhanced (SH, Emax: 34.87 ± 2.98%, pD2: 7.45 ± 0.27; HF, Emax: 34.87 ± 2.98%, pD2: 7.45 ± 0.27; MET, Emax: 85.43 ± 6.80%, pD2: 6.95 ± 0.59, P < 0.001). In HF, the down-regulation of pulmonary ß-ARs results in a significant attenuation of airway relaxation. These effects have been reversed by a treatment with metoprolol, suggesting a potential role of ß-AR blockers in the treatment of patients suffering from HF and chronic obstructive airway diseases.

Bendamustine in combination with ofatumumab in relapsed or refractory chronic lymphocytic leukemia: a GIMEMA Multicenter Phase II Trial.

We conducted a phase II, noncomparative, open-label, multicenter GIMEMA (Gruppo Italiano Malattie EMatologiche dell'Adulto) study (CLL0809) to assess the efficacy and safety of bendamustine in combination with ofatumumab (BendOfa) in relapsed/refractory chronic lymphocytic leukemia (CLL). Forty-seven patients from 14 centers were evaluated. Therapy consisted of bendamustine (70 mg/m(2)) for 2 consecutive days every 28 days, and ofatumumab 300 mg on day 1 and 1000 mg on day 8 during the first cycle, and 1000 mg on day 1 subsequently. Treatment was administered up to six cycles. The overall response rate (ORR), as per intention-to-treat analysis, was 72.3% (95% confidence of interval (CI), 57-84%), with 17% complete responses. After a median follow-up of 24.2 months, the overall survival was 83.6% (95% CI, 73.0-95.7%) and the progression-free survival (PFS) was 49.6% (95% CI, 35.9-68.6%). The median PFS was 23.6 months. Univariate and multivariate analyses were used to identify clinical and biological characteristics associated with ORR and PFS. Myelosuppression was the most common toxicity; grade ≥3 neutropenia was observed in 61.7% of patients; however, grade ≥3 infections occurred in 6% of patients. BendOfa is feasible and effective in relapsed/refractory CLL patients, including patients with high-risk clinical and biological features.

Mitral valve endocarditis in a severe burn patient.

The authors describe the case of a 40-year-old female with severe burns (85% of total body surface area including the thorax) caused by thermal injury who presented mitral valve endocarditis during intensive care unit stay. Bacterial endocarditis represents a rare cause of fatal septicemia complicating thermal injury. The authors focus on diagnosis and on timing of surgical treatment.

Analgesia, sedation, and memory of intensive care.

PURPOSE: The purpose of this article was to investigate the relationship between analgesia, sedation, and memory of intensive care. PATIENTS AND METHODS: One hundred fifty-two adult, cooperative intensive care unit (ICU) patients were interviewed 6 months after hospital discharge about their memory of intensive care. The patient was considered to be cooperative when he/she was aware of self and environment at the interview. The patients were grouped as follows: A (45 patients) substantially no sedation, B (85) morphine, and C (22) morphine and other sedatives. RESULTS: The patients having no memory of intensive care were 38%, 34%, and 23% respectively, in the three groups. They were less ill, according to SAPS II (P <.05), and had a shorter ICU stay (P <.01). Group C patients were more seriously ill according to SAPS II, duration of mechanical ventilation, and length of stay in ICU and in hospital (P <.001). The incidence of factual, sensation, and emotional memories was not different among the three groups. Females reported at least one emotional memory more frequently than males (odds ratio 4.17; 95% CI 10.97-1.59). CONCLUSIONS: The patients receiving sedatives in the ICU are not comparable with those receiving only opiates or nothing, due to the different clinical condition. The lack of memory of intensive care is present in one third of patients and is influenced more by length of stay in ICU than by the sedation received. Sedation does not influence the incidence of factual, sensation, and emotional memories of ICU admitted patients. Females have higher incidences of emotional memories than males.

Quality of life before intensive care admission: agreement between patient and relative assessment.

OBJECTIVE: To assess the agreement between patients and relatives concerning the formers' quality of life (QOL) before intensive care unit (ICU) admission. DESIGN: Prospective study involving direct interviews of patients and relatives during ICU stay. SETTING: Two four-bed surgical-medical ICUs in a 960-bed teaching hospital. PATIENTS AND METHODS: A hundred seventy-two adult, co-operative patients consecutively admitted to ICU for more than 24 h, and their relatives were interviewed. The instruments used were two questionnaires suitable for ICU patients: QOL-IT and QOL-SP. Interobserver reproducibility was investigated in 36 patients. RESULTS: Interobserver reproducibility was nearly perfect (weighted Kappa 0.99 for QOL-IT and QOL-SP). Considering global scores, weighted Kappa was 0.78 for QOL-IT and 0.82 for QOL-SP, with the mean difference between patients and relatives lower than 0.3 for both scores but with limits of agreement wider than 4. Among the items, concordance was excellent in the areas of physical activity and social life for both questionnaires. Gender, living together with the patient and the degree of relationship of relatives did not influence the agreement. CONCLUSIONS: The relatives give global scores for both instruments which can be regarded as acceptable substitutes for those given by patients. However, the wide limits of agreement should make investigators cautious in analysing together scores generated by patients and by relatives. The emotional dimension seems to be assessed less accurately by relatives than the physical one.

Validation of two quality of life questionnaires suitable for intensive care patients.

OBJECTIVE: To validate two instruments measuring quality of life (QOL) suitable for patients admitted to the intensive care unit (ICU): QOL-IT and QOL-SP. DESIGN: Prospective study using patient interviews. SETTING: Two four-bed surgical-medical ICUs in a 960-bed teaching hospital. PATIENTS AND METHODS: One hundred seventy-two adult, co-operative patients consecutively admitted to ICU for more than 24 h were interviewed. One year after hospital discharge, 84 survivors were interviewed again. Inter-observer reproducibility was investigated in 36 patients. To validate the instruments, the QOL-IT and QOL-SP scores reported by patients were considered according to the functional limitation evaluated by the interviewer. Moreover, the theoretical prediction that patients with chronic diseases should have a worse QOL before ICU admission than patients with only acute illness was tested. QOL-IT and QOL-SP scores given 1 year after hospital discharge were compared with those recorded at the first interview. RESULTS: Inter-observer reproducibility was excellent. The possible range of QOL-IT is 0-20 and that of QOL-SP 0-29. According to the functional limitation (absent, mild or severe), the median QOL-IT score increased from 3 to 6 to 13 and QOL-SP from 2 to 6 to 12 (p< 0.0001). The patients with chronic diseases gave scores significantly higher than the patients with only acute illness (median QOL-IT 8 versus 3, p< 0.013; QOL-SP 8 versus 4, p< 0.004). The median QOL-IT score changed from 3 to 4 one year after hospital discharge, a difference which is statistically (p< 0.001), but not clinically, significant. The median QOL-SP score was 3 and did not change. CONCLUSIONS: QOL-IT and QOL-SP are instruments able to discriminate between different health states.

Severe asthma and ARDS triggered by acute short-term exposure to commonly used cleaning detergents.

This report presents a case of severe asthmatic attack and adult respiratory distress syndrome, which occurred in an asthmatic subject following acute short-term exposure to commonly used cleaning detergents. Premorbid lung conditions, i.e. asthma and airway hyperresponsiveness, might have been risk factors for illness severity but not for persistent complaints. This case report indicates that nonindustrial exposures due to household product misuse, especially to mixing cleaning agents, may cause adult respiratory distress syndrome and not only irritant-induced asthma.

Gemcitabine plus vinorelbine in elderly or unfit patients with non-small cell lung cancer.

Cisplatin-based combinations are efficacious in increasing the overall survival of patients with non-small cell lung cancer (NSCLC), but their toxicity makes them unsuitable for elderly and unfit patients. The primary objective of this non-randomized phase II study was to evaluate the feasibility and activity of the gemcitabine plus vinorelbine combination in previously untreated elderly and/or unfit patients with measurable stage III or IV NSCLC. Forty-three patients aged >/= 65 years or with contraindications against cisplatin treatment (36 males and seven females: median age 66 years; range 48-75: PS 0 = 11, PS 1 = 19, PS 2 = 13) received intravenous (i.v.) gemcitabine 1000 mg m(-2), followed by vinorelbine 25 mg m(-2)i.v. on day 1 and 8 every 21 days. Fifteen patients (34.9%) achieved partial remission (confidence interval: 27. 6-42.2%) for a median duration of 6 months; the median survival of these patients has not yet been reached. A further 15 had stable disease for a median of 4 months and a median survival of 7 months. The 10 patients (23.2%) who experienced disease progression had a median survival of 4 months. Three patients are not evaluable. The 1-year actuarial survival rate is 31.1%. The treatment was well tolerated: only 35% of the patients had grade 3 or 4 granulocytopenia on day 14, none experienced episodes of neutropenic fever, and there was no evidence of severe haematological toxicity upon recycling. Only 9% of the patients suffered from gastrointestinal toxicity (grade 3); increased but reversible transaminase levels were observed in 11.6%. In conclusion, the results of this phase II study show that the combination of gemcitabine and vinorelbine is active and well tolerated in NSCLC, and thus encourage its use in elderly or unfit patients.

[Laryngeal mask vs tracheal tube in pediatric anesthesia in the presence of upper respiratory tract infection]. / Maschera laringea vs tubo orotracheale in anestesia pediatrica nella flogosi delle prime vie aeree.

BACKGROUND: The aim of this report is to assess the incidence of postoperative respiratory complications in patients recently suffering from inflammation of the upper respiratory tract in whom a LMA or an uncuffed orotracheal tube have been used. METHODS: Four hundred patients were enrolled aged 6 months to 12 years undergoing general anaesthesia for elective body surface surgery with insertion of the LMA (group M) or the uncuffed tube (group T). Acute inflammation of the upper airways (URI) was assessed, defined by the presence of at least two of the following symptoms, rhinorrhea, coughing, pharyngodynia, disphony, fever, malaise. The appearance of post-surgical adverse respiratory events (ARE), such as laryngospasm, stridor, disphony, excessive coughing was detected. Patients were divided into four groups in relation to the management of the airway and the presence or otherwise of URI (M URI, M NO URI, T URI, T NO URI). RESULTS: In NO URI patients, the presence of ARE was 9.6% in the M and 36.9% in the T group (p < 0.001); in URI patients, these figures were respectively 31.5% and 73.9% (p < 0.001). CONCLUSIONS: The frequency of ARE increases significantly in URI patients with both LMA and the tracheal tube, but with the former is far lower than with the latter. Despite the appearance of only minor and transient complications, it is confirmed that the tracheal intubation is an additional risk factor as a result of the mechanical airway simulation. In recent URI, it would seem appropriate to avoid tracheal intubation, if possible, preferring the LMA.

Predictors of weaning outcome in chronic obstructive pulmonary disease patients.

Several threshold values for predicting weaning outcome from mechanical ventilation have been proposed. These values, however, have been obtained in nonhomogeneous patient populations. The aim of the present study was to determine the threshold values in chronic obstructive pulmonary disease (COPD) patients and compare them to those reported for nonhomogeneous patient populations. The initial weaning trial included 81 COPD patients. Fifty-three of them underwent a successful weaning trial, whereas 28 failed it. The latter were enrolled into the present investigation, and were restudied during a subsequent successful trial. The weaning indices used were those reported in the literature. The threshold values obtained were within 10% of those reported for a nonhomogeneous patients population only for tidal volume and effective compliance. The classification error was <20% for maximal inspiratory pressure (MIP), occluded inspiratory pressure swing (deltaPI)/MIP, rapid and shallow breathing (respiratory frequency/tidal volume), and compliance, rate, oxygenation, pressure index (CROP), whereas the area under the receiver operating characteristic curves was >0.9 only for deltaPI/MIP and CROP. In conclusion, the threshold values obtained in chronic obstructive pulmonary disease patients who failed the first weaning attempt differed from those previously reported. Although a gold standard weaning index is not available for chronic obstructive pulmonary disease patients, the occluded inspiratory pressure swing/ maximal inspiratory pressure and compliance, rate, oxygenation, pressure index may be candidates for such a role.

Presumptive delayed gas embolism after laparoscopic cholecystectomy.

A 50-year-old woman, with a history of arterial hypertension treated with beta-blocker and Ca-antagonist, presented cardiac arrest 6 hours after elective laparoscopic cholecystectomy. During surgical intervention, arterial hypotension without any respiratory change was observed. Dyspnea, asthenia and anxiety were the clinical signs appearing approximately 2 hours before cardiac arrest. After resuscitation, myocardial infarction, dissecting thoracic aortic aneurysm and major pulmonary thromboembolism were excluded. The signs of increased resistance to the right ventricular outflow and the relevant alteration of coagulation tests, lasting only a few hours, suggested venous gas embolism. Subsequently, the patient presented a cortical blindness, persisting at hospital discharge. The anesthetists should be aware about the complication that we observed after laparoscopic surgery. The least sign of cardiorespiratory instability appearing in the postoperative period must be taken into account and signal the need for increased monitoring.

Validation of severity scoring systems SAPS II and APACHE II in a single-center population.

OBJECTIVE: To validate two severity scoring systems, the Simplified Acute Physiology Score (SAPS II) and Acute Physiology and Chronic Health Evaluation (APACHE II), in a single-center ICU population. DESIGN AND SETTING: Prospective data collection in a two four-bed multidisciplinary ICUs of a teaching hospital. PATIENTS AND METHODS: Data were collected in ICU over 4 years on 1,721 consecutively admitted patients (aged 18 years or older, no transferrals, ICU stay at least 24 h) regarding SAPS II, APACHE II, predicted hospital mortality, and survival upon hospital discharge. RESULTS: At the predicted risk of 0.5, sensitivity was 39.4 % for SAPS II and 31.6 % for APACHE II, specificity 95.6 % and 97.2 %, and correct classification rate 85.6 % and 85.5 %, respectively. The area under the ROC curve was higher than 0.8 for both models. The goodness-of-fit statistic showed no significant difference between observed and predicted hospital mortality (H = 7.62 for SAPS II, H = 3.87 for APACHE II; and C = 9.32 and C = 5.05, respectively). Observed hospital mortality of patients with risk of death higher than 60 % was overpredicted by SAPS II and underpredicted by APACHE II. The observed hospital mortality was significantly higher than that predicted by the models in medical patients and in those admitted from the ward. CONCLUSIONS: This study validates both SAPS II and APACHE II scores in an ICU population comprised mainly of surgical patients. The type of ICU admission and the location in the hospital before ICU admission influence the predictive ability of the models.

Respiratory mechanics during and after anaesthesia for major vascular surgery.

To evaluate the effects of major vascular surgery on respiratory mechanics, 11 patients undergoing general anaesthesia for abdominal aortic surgery were studied. Before aortic cross-clamping, chest wall elastance and resistance both increased (by 126% and 58%, respectively) when surgical retractors were placed. After aortic cross-clamping, lung elastance increased by 29%, accompanied by a decrease in cardiac index (22%) and an increase in pulmonary (17%) and systemic (15%) vascular resistance. After aortic unclamping, lung elastance decreased, although it remained higher than baseline values (by 12%). All cardiovascular variables returned to the values obtained before aortic cross-clamping.

Respiratory effects of pharingeal gas insufflation in patients with chronic obstructive pulmonary disease.

OBJECTIVE: To evaluate the effects of pharyngeal gas insufflation (PGI) in clinically stable patients with chronic obstructive pulmonary disease (COPD). DESIGN: Prospective study in humans. SETTING: Department of Intensive Care Medicine at a University Hospital. PATIENTS: Seven clinically stable COPD patients. INTERVENTION: Pharyngeal dry fresh air insufflation (PGI) with a continuous flow rate of 4 L/min was given via a nasal catheter placed into the oropharynx. Baseline measurements with zero flow were made at the beginning and end of the test. After an equilibration period of 1 h at each stage, arterial blood samples were analyzed every 5 min until PaCO2 variation less than 5% confirmed the achievement of a steady state. Thereafter expiratory flow signal and expiratory gas were collected over a period of 3 min and arterial blood was sampled after 1'30" and 2'30" from the beginning of the test for the measurement of effective expiratory volume (VE eff), respiratory rate (RR), tidal volume (VT), dead space fraction (VD/VT), dead space (VD), alveolar ventilation (VA), total expiratory time (TE min), and PaCO2, respectively. RESULTS: During PGI VT, VD/VT, VD and VE eff fell significantly from baseline values, RR was slightly reduced and VA, TE min and PaCO2 remained unchanged throughout the study. CONCLUSIONS: Although in our study the effect of PGI on VD could be overestimated since our device for expiratory gas flow measurement and collection significantly enlarged the anatomical dead space receiving the washout effect of the fresh gas insufflation, under the experimental conditions PGI produces a reduction in VD and VD/VT, and, as a consequence, a significative reduction in respiratory requirements in clinically stable COPD patients. If confirmed in clinical settings, potential advantages of PGI could include: a) reduction of the work of breathing in patients with intact neuro-respiratory coupling; b) minimizing hypercapnic side effects of oxygen therapy often seen in COPD patients.