High response rate and improved exercise capacity and quality of life with a new regimen of darbepoetin alfa with or without filgrastim in lower-risk myelodysplastic syndromes: a phase II study by the GFM.

Darbepoetin (DAR), with or without granulocyte colony-stimulating factor (G-CSF), has proved effective in treating anemia in patients with lower-risk myelodysplastic syndrome (MDS), but its effects on quality of life (QoL) and exercise functioning are less well established. In this phase II study (no. NCT00443339), lower-risk MDS patients with anemia and endogenous erythropoietin (EPO) level <500 IU/L received DAR 500 µg once every 2 weeks for 12 weeks, with G-CSF added at week 12 in non-responders. Physical performance was assessed with the 6-min walking test and, for fit patients, maximal oxygen consumption (VO2max). QoL was evaluated using SF-36 and FACT-An tests. In 99 patients, erythroid response rate according to IWG 2006 criteria was 48 and 56 % at 12 and 24 weeks, respectively. Addition of G-CSF rescued 22 % of non-responders. In 48 % of the responders, interval between darbepoetin injections could be increased for maintenance treatment. Serum EPO level was the only independent predictive factor of response at 12 weeks, and its most discriminant cutoff value was 100 IU/L. QoL and VO2max showed improvement over time in responders, compared with non-responders. With a median follow-up of 52 months, median response duration was not reached, and 3-year cumulative incidence of acute myeloid leukemia and overall survival (OS) was 14.5 and 70 %, respectively. Baseline transfusion dependence, International Prognostic Score System (IPSS), and Revised IPSS accurately predicted OS from treatment onset. Tolerance of darbepoetin was good. In conclusion, this regimen of darbepoetin every 2 weeks yielded high response rates and prolonged response duration. Objective improvement in exercise testing and in patient-reported QoL confirms the clinical relevance of anemia correction with erythropoiesis-stimulating agents.

Cardiovascular responses during hypoventilation at exercise.

This study aimed to determine the cardiovascular responses during a prolonged exercise with voluntary hypoventilation (VH). 7 men performed 3 series of 5-min exercise at 65% of normoxic maximal O (2) uptake under 3 conditions: (1) normal breathing (NB) in normoxia (NB (0.21)), (2) VH in normoxia (VH (0.21)), (3) NB in hypoxia (NB (0.157), inspired oxygen fraction=0.157). In both VH (0.21) and NB (0.157), there was a similar drop in arterial oxygen saturation and arterial O (2) content (CaO (2)) which were lower than in NB (0.21). Heart rate (HR), stroke volume, and cardiac output (-) were higher in VH (0.21) than in NB (0.21) during most parts of exercise whereas there was no difference between NB (0.157) and VH (0.21) or NB (0.21). HR variability analysis suggested an increased sympathetic modulation in VH (0.21) only. O (2) transport and oxygen uptake were generally not different between interventions. Mixed venous O (2) content (C-O (2)) was lower in NB (0.157) than in both VH (0.21) and NB (0.21) and not different between the latter. CaO (2)-C-O (2) was not different between NB (0.157) and NB (0.21) but lower in VH (0.21). This study shows that a prolonged exercise with VH leads to a greater cardiac activity, independent from the hypoxic effect. The greater - in VH compared to normal breathing seems to be the main factor for compensating the drop of arterial oxygen content.

Short- and long-term response to corticosteroid therapy in chronic beryllium disease.

Chronic beryllium disease (CBD) is a granulomatous disorder that affects the lung after exposure to beryllium. The present study reports short- and long-term evolution of granulomatous and fibrotic components in eight patients with severe CBD receiving corticosteroid therapy. Eight patients with confirmed CBD were studied at baseline, after initial corticosteroid treatment (4-12 months), at relapse and at the final visit. Beryllium exposure, Glu(69) (HLA-DPB1 genes coding for glutamate at position beta69) polymorphism, symptoms, pulmonary function tests (PFT), serum angiotensin-converting enzyme (SACE) and high-resolution computed tomography (HRCT) quantification of pulmonary lesions were analysed. The CBD patients were observed for a median (range) of 69 (20-180) months. After stopping beryllium exposure, corticosteroids improved symptoms and PFT (vital capacity +26%, diffusing capacity of the lung for carbon monoxide +15%), and decreased SACE level and active lesion HRCT score. In total, 18 clinical relapses occurred after the treatment was tapered and these were associated with SACE and active lesion HRCT score impairment. At the final visit, corticosteroids had completely stabilised all parameters including both HRCT scores of active lesions and fibrotic lesions in six out of eight patients. Corticosteroids were beneficial in chronic beryllium disease. They were effective in suppressing granulomatosis lesions in all cases and in stopping the evolution to pulmonary fibrosis in six out of eight patients.

Acute adrenal insufficiency associated with heparin-induced thrombocytopenia.

Although the thrombotic risk of heparin-induced thrombocytopaenia (HIT) is well recognized and may affect any vascular bed, the involvement of adrenal veins has been less commonly described. We report the case of a 86-year-old woman who developed bilateral massive adrenal haematoma associated with HIT, resulting in acute adrenal insufficiency. After immediate discontinuation of heparin and starting therapy with danaparoid and hydrocortisone, the clinical evolution was favourable, although adrenal failure was irreversible. When abdominal pain, hypotension and fever occur during heparin therapy, associated with a drop in platelet count, acute adrenal insufficiency secondary to HIT should be considered, as early diagnosis is essential for the treatment of this life-threatening complication.

Moderate exercise in hypoxia induces a greater arterial desaturation in trained than untrained men.

During moderate exercise breathing a low inspired O(2) fraction (F(I)O(2)), arterial O(2) desaturation may depend on the fitness level. Seven trained (TM) and seven untrained men (UTM) cycled in normoxia and in hypoxia (F(I)O(2)=0.187, 0.173, 0.154, 0.13 and 0.117). We compared TM and UTM at submaximal intensities below the ventilatory threshold. Ventilatory variables were monitored and arterial oxygen saturation was measured by pulse oximetry. O(2) saturation was not different between groups at sea level. In hypoxia, O(2) saturation was lower in TM than in UTM at F(I)O(2)=0.154 (87.3 +/- 2.9% vs 90.4 +/- 1.5% at 90 W) and below. Both the ventilatory-equivalent and the end-tidal O(2) pressure were lower in TM at sea level and at every F(I)O(2), with the differences between TM and UTM becoming apparent at lower exercise intensity and increasing in magnitude as the severity of hypoxia increased. O(2) saturation was correlated with the ventilatory parameters at every F(I)O(2) and the correlations were stronger in severe hypoxia. These results demonstrate that a moderate exercise carried out in hypoxia, contrary to normoxic conditions, can lead to a greater arterial desaturation in TM compared with UTM. This phenomenon could be partly attributed to a relative hypoventilation in trained subjects.

Role of maximal heart rate and arterial O2 saturation on the decrement of VO2max in moderate acute hypoxia in trained and untrained men.

We aimed to evaluate 1) the altitude where maximal heart rate (HR (max)) decreases significantly in both trained and untrained subjects in moderate acute hypoxia, and 2) if the HR (max) decrease could partly explain the drop of V.O (2max). Seventeen healthy males, nine trained endurance athletes (TS) and eight untrained individuals (US) were studied. Subjects performed incremental exercise tests at sea level and at 5 simulated altitudes (1000, 1500, 2500, 3500, 4500 meters). Power output (PO), heart rate (HR), arterial oxygen saturation (SaO (2)), oxygen uptake (V.O (2)), arterialized blood pH and lactate were measured. Both groups showed a progressive reduction in V.O (2max). The decrement in HR (max) (DeltaHR (max)) was significant from 1000 m for TS and 2500 m for US and more important in TS than US (at 1500 m and 3500 m). At maximal exercise, TS had a greater reduction in SaO (2) (DeltaSaO (2)) at each altitude. DeltaHR (max) observed in TS was correlated with DeltaSaO (2). When the two groups were pooled, simple regressions showed that DeltaV.O (2max) was correlated with both DeltaSaO (2) and DeltaHR (max). However, a multiple regression analysis demonstrated that DeltaSaO (2) alone may account for DeltaV.O (2max). Furthermore, in spite of a greater reduction in SaO (2) and HR (max) in TS, no difference was evidenced in relative DeltaV.O (2max) between groups. Thus, in moderate acute hypoxia, the reduction in SaO (2) is the primary factor to explain the drop of V.O (2max) in trained and untrained subjects.

Measurement of CO2 response with the breath-by-breath automatic acquisition of the breathing pattern and occlusion pressure.

OBJECTIVE: Our objective is to present a methodology for the automated acquisition and storage of BP and P0.1 during a CO2 rebreathing test. METHODS: The system consists of a microcomputer with additional circuits and an automatic electronically controlled valve to occlude the inspiratory airway. Data collection and data processing are separate programs. Airway pressure and flow are digitized at a 100-Hz rate, while PETCO2 is determined and P0.1 is measured on a breath-by-breath basis. Off-line processing calculates the BP variables, generates a correlation matrix (VE/PETCO2, TTOT/PETCO2, TI/PETCO2, TE/PETCO2, [VT/TI]/PETCO2, [TI/TTOT]/PETCO2, P0.1/PETCO2), and edits graphic data. The accuracy of the volume and pressure measurements was tested by comparing known volumes provided by a syringe (n = 100) and a series of pressures controlled by a water manometer (n = 41) on the one hand, with volumes and pressures measured by the device. The accuracy of the time intervals and P0.1 was assessed by comparing in 10 healthy subjects the values measured manually on a graphic recording with those provided by the device (n = 170). RESULTS: Volumes:Vmeasured = 0.99 x Vcontrolled, r = 0.99, p < 0.001. Pressures:Pmeasured = 0.97 x Pcontrolled + 0.09, r = 0.98, p < 0.001. Inspiratory time:TIautomatic = 0.91 x TIgraphic + 0.22, r = 0.93, p < 0.001. Expiratory time:TEautomatic = 0.93 x TEgraphic + 0.34, r = 0.95, p < 0.001. Occlusion pressure:P0.1automatic = 0.95 x P0.1graphic + 0.62, r = 0.94, p < 0.001. Reproducibility was assumed to be represented by the intraindividual coefficient of variation of the CO2 response. The comparison of an automatic breath-to-breath method with a graphic manual recording revealed significantly less variability with the former (VE/PETCO2: 15.2 +/- 4.5% vs 22.5 +/- 6.3%, p < 0.01; P0.1/PETCO2:8.3 +/- 4.3% vs 19.7 +/- 7.2%, p < 0.001; [VT/TI]/PETCO2:9.1 +/- 3.5% vs 14.5 +/- 5.3%, p < 0.05). CONCLUSION: Our automated acquisition and storage of waveforms and breath-by-breath determination of BP and P0.1 provide an easy and thorough analysis of the respiratory response to CO2 and decrease the variability of the results.

Effects of doxapram on hypercapnic response during weaning from mechanical ventilation in COPD patients.

Failure of weaning from mechanical ventilation in COPD patients is often related to diaphragmatic fatigue. Whether there is a central respiratory drive fatigue and a reserve of excitability is still debated. The purpose of this study was to analyze the following in 13 COPD patients weaned from mechanical ventilation: (1) ventilatory (VE/PETCO2) and neuromuscular (P0.1/PETCO2) response to hypercapnia; (2) the maximum reserve capacity measured through changes in the VE/PETCO2 and P0.1/PETCO2 slopes after doxapram (DXP) infusion, which, given during the test, allows measurement of the maximum response capacity to overstimulation; and (3) analyze the influence of these changes on the outcome of weaning. The results show a variable P0.1/PETCO2 response and a low VE/PETCO2. DXP infusion does not change the slopes of these relations but increases the end-expiratory volume (delta FRCd); (p less than 0.02). Since there was no change in the VE/PETCO2, P0.1/PETCO2, and delta FRC values with or without DXP, there was no excitability reserve in patients who were successfully weaned. When weaning failed, DXP did not change VE/PETCO2 and P0.1/PETCO2 slope, but delta FRCd was greater the delta FRC (p less than 0.001). The excitability reserve in these patients leads to an increase in end-expiratory volume, probably worsening the diaphragm dysfunction.

[Hyperoxia test during attempts to withdraw artificial ventilation]. / Test d'hyperoxie au cours des tentatives de sevrage de ventilation artificielle.

A 30 minute test of hyperoxia (10 l.min-1) was conducted in patients (n = 21) with chronic obstructive lung disease during the weaning trials from mechanical ventilation. Two groups were formed according to whether the occlusion pressure at 100 ms (PO.1), index of central stimulation, decreased or not during the test. The first group lowered PO.1 and increased PaCO2 by decreasing VE (minute-ventilation), VA (alveolar ventilation) and increasing the VD/VT ratio; the others had a lower PO.1 and did not modify it after administration of 02 despite a lowered PaO2 initially identical to that in the first group. They held PaCO2 constant by increasing VE and by maintaining VA in relationship with an improvement in diaphragm contractility and/or a better response to hypercapnia stimulus. All the patients is this group were successfully weaned eight days after the study period.

Steady-state breathing pattern responses to small inspiratory resistive loads in COPD patients. Application to weaning from mechanical ventilation.

We investigated the effect of small inspiratory resistive loads on the breathing patterns of patients with COPD admitted to the ICU for acute respiratory failure. Patients were in stable clinical condition three days after weaning from the acute-phase ventilation. Healthy nonsmokers served as controls. Breathing patterns were recorded for 20-min periods during unloaded breathing (R0), then with small inspiratory resistive loads (R1 = 2.5 cmH2O L/s and R2 = 5.2 cmH2O L/s) applied in random order. Respiratory parameters were memorized in real time and blood gases measured continuously with a transcutaneous PO2/PCO2 monitor and compared periodically with arterial blood gases. Minute volume (VE) and respiratory rate decreased with no modification in blood gas values. In the COPD patients, R1 was too small to be perceived; when R2 was applied, no increase in TI was observed, and VT and VT/TI decreased. The VE could not be maintained despite a shortening of expiratory time. The COPD patients did not have significant increase of occlusion pressure (P0.1). Mean blood gas values did not change during the testing, but the coefficient of variation of tcPCO2 increased. During the critical period following weaning from artificial ventilation, COPD patients did not respond in the same manner as normal subjects to inspiratory resistive loads, but did not have modified gas exchange during the 20-min period.

Diaphragmatic fatigue and breathing pattern during weaning from mechanical ventilation in COPD patients.

The medium-term outcome of weaning from mechanical ventilation in COPD patients is not easy to anticipate because a respiratory fatigue may eventually develop. We evaluated the diaphragmatic function and the breathing pattern during 40 weaning trials on 15 patients ventilated after acute respiratory failure. We formed two groups according to the success (group B, n = 18) or failure (group A, n = 19) of the medium-term attempt (group A/less than 10 hours; group B/more than 12 hours). Provided the patients showed the classic weaning criteria (tidal volume greater than 5 ml/kg, respiratory frequency less than 30 breaths per minute, PaO2 greater than 50 mm Hg), the study of the breathing pattern did not allow differentiation between the groups. However, the transdiaphragmatic pressure (Pdi) and the Pdimax, which gave an indication of the power of diaphragm contraction, dropped early in the group that could not stand weaning, with an increase in the Pdi/Pdimax ratio. In addition, this same group showed a diaphragmatic dysfunction attested for by a frequent negative gastric pressure associated with or shortly preceded by an abdominal paradoxic motion.

Respiratory function in recent pulmonary sarcoidosis with special reference to small airways.

This study was designed to evaluate airway dysfunction in relation to duration of disease in patients with pulmonary sarcoidosis for less than two years. Twenty four subjects with recent disease were compared with nine subjects with disease of more than two years' duration. They underwent lung function testing (lung volumes, lung transfer factor for CO and pulmonary mechanics). Small airway function was assessed using frequency dependence of compliance, closing volume, nitrogen single breath test and flow-volume curves breathing air and helium-oxygen mixture. Airway dysfunction was seen in pulmonary sarcoidosis even in some patients with recent disease and it became more evident in disease of longer duration. The results suggest small airway involvement. The frequency of airway dysfunction is difficult to evaluate, varying from estimates of 0% using flow-volume curves to 79% with frequency dependence of compliance. This apparent discrepancy could be explained by the consequences of parenchymal involvement leading to inhomogeneities in distribution of compliance, and of elastic lung recoil. We conclude that patients with recent sarcoidosis are probably affected by intrinsic small airway disease, but an increase in elastic recoil often conceals its consequences. The airway disease may not be apparent using conventional function tests and published predicted values.