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1.  COPD exacerbations · 5: Management 
Thorax  2006;61(6):535-544.
A review of the most relevant evidence based therapeutic options currently available for the management of exacerbations of COPD
doi:10.1136/thx.2005.041863
PMCID: PMC2111219  PMID: 16738044
chronic obstructive pulmonary disease; exacerbations; management
2.  Prognostic factors influencing the outcome in pneumocystis carinii pneumonia in patients with AIDS. 
Thorax  1995;50(6):668-671.
BACKGROUND--Studies attempting to identify the prognostic factors that influence the outcome of Pneumocystis carinii pneumonia (PCP) in patients with AIDS using a multivariate analysis are few. In order to identify those prognostic factors amenable to medical intervention, univariate and multivariate analyses were performed on 102 patients with AIDS suffering a first episode of PCP. METHODS--One hundred and two consecutive patients with AIDS (51% drug abusers, 45% homosexuals, and 4% with other HIV risk factors) admitted to our institution between 1986 and 1989 whose respiratory infection was diagnosed by bronchoalveolar lavage were studied prospectively. RESULTS--The overall mortality was 28%, rising to 79% in those patients who required mechanical ventilation. According to univariate analysis the following variables were related to a poor prognosis: age > 35 years; risk factor for HIV infection other than drug abuse; and AIDS diagnosis confirmed before 1988; PaO2 < 8 kPa at admission; severe acute respiratory failure on admission (PaO2/FIO2 < 20 kPa); mechanical ventilation; antibiotic therapy for PCP other than trimethoprim-sulphamethoxazole; multiple microbial pulmonary infection; serum lactate dehydrogenase (LDH) > 22.5 mukat/l on admission; serum albumin level < 30 g/l. Multivariate analysis showed that only mechanical ventilation was independently associated with a poor outcome. CONCLUSIONS--The mortality of AIDS patients presenting with a first episode of PCP before 1990 was high (28%). The main prognostic factor associated with poor outcome was the requirement for mechanical ventilation due to severe acute respiratory failure.
PMCID: PMC1021269  PMID: 7638811
3.  Cellular bioenergetics after erythropoietin therapy in chronic renal failure. 
Journal of Clinical Investigation  1996;97(9):2101-2110.
After erythropoietin (rHuEPO) therapy, patients with chronic renal failure (CRF) do not improve peak O2 uptake (VO2 peak) as much as expected from the rise in hemoglobin concentration ([Hb]). In a companion study, we explain this phenomenon by the concurrent effects of fall in muscle blood flow after rHuEPO and abnormal capillary O2 conductance observed in CRF patients. The latter is likely associated with a poor muscle microcirculatory network and capillary-myofiber dissociation due to uremic myopathy. Herein, cellular bioenergetics and its relationships with muscle O2 transport, before and after rHuEPO therapy, were examined in eight CRF patients (27 +/- 7.3 [SD] yr) studied pre- and post-rHuEPO ([Hb] = 7.8 +/- 0.7 vs. 11.7 +/- 0.7 g x dl-1) during an incremental cycling exercise protocol. Eight healthy sedentary subjects (26 +/- 3.1 yr) served as controls. We hypothesize that uremic myopathy provokes a cytosolic dysfunction but mitochondrial oxidative capacity is not abnormal. 31P-nuclear magnetic resonance spectra (31P-MRS) from the vastus medialis were obtained throughout the exercise protocol consisting of periods of 2 min exercise (at 1.67 Hz) at increasing work-loads interspersed by resting periods of 2.5 min. On a different day, after an identical exercise protocol, arterial and femoral venous blood gas data were obtained together with simultaneous measurements of femoral venous blood flow (Qleg) to calculate O2 delivery (QO2leg) and O2 uptake (VO2leg). Baseline resting [phosphocreatine] to [inorganic phosphate] ratio ([PCr]/[Pi]) did not change after rHuEPO (8.9 +/- 1.2 vs. 8.8 +/- 1.2, respectively), but it was significantly lower than in controls (10.9 +/- 1.5) (P = 0.01 each). At a given submaximal or peak VO2leg, no effects of rHuEPO were seen on cellular bioenergetics ([PCr]/[Pi] ratio, %[PCr] consumption halftime of [PCr] recovery after exercise), nor in intracellular pH (pHi). The post-rHuEPO bioenergetic status and pHi, at a given VO2leg, were below those observed in the control group. However, at a given pHi, no differences in 31P-MRS data were detected between post-rHuEPO and controls. After rHuEPO, at peak VO2, Qleg fell 20% (P < 0.04), limiting the change in QO2leg to 17%, a value that did not reach statistical significance. The corresponding O2 extraction ratio decreased from 73 +/- 4% to 68 +/- 8.2% (P < 0.03). These changes indicate that maximal O2 flow from microcirculation to mitochondria did not increase despite the 50% increase in [Hb] and explain how peak VO2leg and cellular bioenergetics (31P-MRS) did not change after rHuEPO. Differences in pHi, possibly due to lactate differences, between post-rHeEPO and controls appear to be a key factor in the abnormal muscle cell bioenergetics during exercise observed in CRF patients.
PMCID: PMC507285  PMID: 8621800
4.  Effects of erythropoietin on muscle O2 transport during exercise in patients with chronic renal failure. 
Journal of Clinical Investigation  1996;97(9):2092-2100.
Erythropoietin (rHuEPO) has proven to be effective in the treatment of anemia of chronic renal failure (CRF). Despite improving the quality of life, peak oxygen uptake after rHuEPO therapy is not improved as much as the increase in hemoglobin concentration ([Hb)] would predict. We hypothesized that this discrepancy is due to failure of O2 transport rates to rise in a manner proportional to [Hb]. To test this, eight patients with CRF undergoing regular hemodialysis were studied pre- and post-rHuEPO ([Hb] = 7.5 +/- 1.0 vs. 12.5 +/- 1.0 g x dl-1) using a standard incremental cycle exercise protocol. A group of 12 healthy sedentary subjects of similar age and anthropometric characteristics served as controls. Arterial and femoral venous blood gas data were obtained and coupled with simultaneous measurements of femoral venous blood flow (Qleg) by thermodilution to obtain O2 delivery and oxygen uptake (VO2). Despite a 68% increase in [Hb], peak VO2 increased by only 33%. This could be explained largely by reduced peak leg blood flow, limiting the gain in O2 delivery to 37%. At peak VO2, after rHuEPO, O2 supply limitation of maximal VO2 was found to occur, permitting the calculation of a value for muscle O2 conductance from capillary to mitochondria (DO2). While DO2 was slightly improved after rHuEPO, it was only 67% of that of sedentary control subjects. This kept maximal oxygen extraction at only 70%. Two important conclusions can be reached from this study. First, the increase in [Hb] produced by rHuEPO is accompanied by a significant reduction in peak blood flow to exercising muscle, which limits the gain in oxygen transport. Second, even after restoration of [Hb], O2 conductance from the muscle capillary to the mitochondria remains considerably below normal.
PMCID: PMC507284  PMID: 8621799
5.  The hepatopulmonary syndrome: new name, old complexities. 
Thorax  1992;47(11):897-902.
On the basis of previous work, our own experience and findings, and the considerations discussed above, we propose a set of four diagnostic criteria for the hepatopulmonary syndrome: 1. presence of chronic hepatic disease (alcoholic, postnecrotic, or primary biliary cirrhosis or active chronic hepatitis)--severe liver dysfunction may not be mandatory; 2. absence of intrinsic cardiopulmonary disease, with normal chest radiograph or with nodular basal shadowing; 3. pulmonary gas exchange abnormalities--an increased alveolar-arterial oxygen gradient (> or = 2.0 kPa) with or without hypoxaemia; 4. the extrapulmonary appearance of intravenous radiolabelled microspheres or a positive contrast enhanced echocardiogram, suggesting intrapulmonary vascular abnormalities. Although these four criteria appear straightforward, there may be other features that are not always present--namely: 1. low transfer factor (diffusing capacity); 2. shortness of breath, with or without platypnoea and orthodeoxia; 3. increased cardiac output and reduced pulmonary vascular pressures; 4. small (or no) increase in pulmonary vascular resistance when the patient is breathing low oxygen mixtures. From the physiological viewpoint, the hepatopulmonary syndrome provides an excellent model for clinical research in the pathophysiology of pulmonary gas exchange. So far it has been possible to show that arterial hypoxaemia in this condition is (1) partitioned into components resulting from VA/Q mismatching, intrapulmonary shunt, and limitations of oxygen diffusion; (2) modulated by the interplay between the intrapulmonary and the extrapulmonary determinants of PaO2, such as cardiac output and minute ventilation; (3) vulnerable to the influence of inadequate pulmonary vascular tone; and (4) resolved when the injured liver is replaced and hepatic function is restored to within normal limits.
PMCID: PMC464086  PMID: 1465744

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