Last 3 months of life in home-ventilated patients: the family perception.

We studied the family's perception of care in patients under home mechanical ventilation during the last 3 months of life. In 11 respiratory units, we submitted a 35-item questionnaire to relatives of 168 deceased patients exploring six domains: symptoms, awareness of disease, family burden, dying, medical and technical problems. Response rate was 98.8%. The majority of patients complained respiratory symptoms and were aware of the severity and prognosis of the disease. Family burden was high especially in relation to money need. During hospitalisation, 74.4% of patients were admitted to the intensive care unit (ICU). 78 patients died at home, 70 patients in a medical ward and 20 in ICU. 27% of patients received resuscitation manoeuvres. Hospitalisations and family economical burden were unrelated to diagnosis and mechanical ventilation. Families of the patients did not report major technical problems on the use of ventilators. In comparison with mechanical invasively ventilated patients, noninvasively ventilated patients were more aware of prognosis, used more respiratory drugs, changed ventilation time more frequently and died less frequently when under mechanical ventilation. We have presented good points and bad points regarding end-of-life care in home mechanically ventilated patients. Noninvasive ventilation use and diagnosis have impact on this burden.

End-of-life decision-making in respiratory intermediate care units: a European survey.

A survey was performed on behalf of the European Respiratory Society to assess end-of-life practices in patients admitted to European respiratory intermediate care units and high dependency units over a 6-month period. A 33-item questionnaire was sent by e-mail to physicians throughout Europe and the response rate was 28 (29.5%) out of 95. A total of 6,008 patients were admitted and an end-of-life decision was taken in 1,292 (21.5%). The mortality rate in these patients was 68% (884 out of 1,292). The patients received similar proportions of withholding of treatment (298 (23%) out of 1292), do-not-resuscitate or do-not-intubate orders (442 (34%) out of 1,292) and noninvasive mechanical ventilation as the ceiling of ventilatory care (402 (31%) out of 1,292). Withdrawal of therapy was employed in 149 (11%) out of 1,292 patients and euthanasia in one. Do-not-intubate/do-not-resuscitate orders were more frequently used in North compared with South Europe. All of the 473 competent patients directly participated in the decision, whereas, in 722 (56%) out of 1,292 cases, decision-making was reported to be shared with the nurses. In European respiratory intermediate care units and high dependency units, an end-of-life decision is taken for 21.5% of patients admitted. Withholding of treatment, do-not-intubate/do-not-resuscitate orders and noninvasive mechanical ventilation as the ventilatory care ceiling are the most common procedures. Competent patients are often involved, together with nurses.

The Italian multicentre study on noninvasive ventilation in chronic obstructive pulmonary disease patients.

Chronic obstructive pulmonary disease (COPD) patients with chronic ventilatory failure (CVF) are more likely to develop exacerbations, which are an important determinant of health-related quality of life (HRQL). Long-term noninvasive positive-pressure ventilation (NPPV) has been proposed in addition to long-term oxygen therapy (LTOT) to treat CVF but little information is available on its effects on HRQL and resource consumption. Therefore, the current authors undertook a 2-yr multicentric, prospective, randomised, controlled trial to assess the effect of NPPV+ LTOT on: 1) severity of hypercapnia; 2) use of healthcare resources, and 3) HRQL, in comparison with LTOT alone. One hundred and twenty-two stable hypercapnic COPD patients on LTOT for > or = 6 months were consecutively enrolled. After inclusion and 1-month run-in, 90 patients were randomly assigned to NPPV+LTOT (n=43) or to LTOT alone (n=47). Arterial blood gases, hospital and intensive care unit (ICU) admissions, total hospital and ICU length of stay and HRQL were primary outcome measures; survival and drop-out rates, symptoms (dyspnoea and sleep quality) and exercise tolerance were secondary outcome measures. Follow-up was performed at 3-month intervals up to 2 yrs. Lung function, inspiratory muscle function, exercise tolerance and sleep quality score did not change over time in either group. By contrast the carbon dioxide tension in arterial blood on usual oxygen, resting dyspnoea and HRQL, as assessed by the Maugeri Foundation Respiratory Failure Questionnaire, changed differently over time in the two groups in favour of NPPV+LTOT. Hospital admissions were not different between groups during the follow-up. Nevertheless, overall hospital admissions showed a different trend to change in the NPPV+LTOT (decreasing by 45%) as compared with the LTOT group (increasing by 27%) when comparing the follow-up with the follow-back periods. ICU stay decreased over time by 75% and 20% in the NPPV+LTOT and LTOT groups, respectively. Survival was similar. Compared with long-term oxygen therapy alone, the addition of noninvasive positive-pressure ventilation to long-term oxygen therapy in stable chronic obstructive pulmonary disease patients with chronic ventilatory failure: 1) slightly decreased the trend to carbon dioxide retention in patients receiving oxygen at home and 2) improved dyspnoea and health-related quality of life. The results of this study show some significant benefits with the use of nocturnal, home noninvasive positive-pressure ventilation in patients with chronic ventilatory failure due to advanced chronic obstructive pulmonary disease patients. Further work is required to evaluate the effect of noninvasive positive-pressure ventilation on reducing the frequency and severity of chronic obstructive pulmonary disease exacerbation.

Outcome of COPD patients performing nocturnal non-invasive mechanical ventilation.

The role of non-invasive nocturnal domiciliary ventilation (NNV) in chronic obstructive pulmonary disease (COPD) patients with chronic hypercapnia is still discussed. The aims of this study were to evaluate the long-term survival, the clinical effectiveness and side-effects of NNV in these patients. Forty-nine stable hypercapnic COPD patients on long-term oxygen therapy (LTOT) were assigned to two groups: in Group 1, 28 patients performed NNV by pressure support modality in addition to LTOT; in Group 2, 21 patients continued their usual LTOT regimen. Treatment was assigned according to the compliance to NNV, after an in hospital period. Mortality rate, hospital stay (HS) and ICU admissions (IA) were recorded in the two groups. HS and IA were compared to those recorded in a similar period of follow-back. Lung and respiratory muscle function, dyspnoea, and exercise capacity (by 6-min walk test) were evaluated baseline and every 3-6 months up to 3 yr. Mean follow-up time was 35 +/- 7 months. Mortality rate was not different between the two groups: 16, 33, 46% and 13, 28, 50% at 1, 2 and 3 yr in Groups 1 and 2 respectively. Lung and respiratory muscle function did not significantly change over time. A significant increase in 6-min walk test (from 245 +/- 78 to 250 +/- 88, 291 +/- 75, 284 +/- 89 m after 1, 2 and 3 yr respectively, P < 0.01) was observed only in patients undergoing NNV. In comparison to the follow back HS significantly decreased in both groups (from 37 +/- 29 to 15 +/- 12 and from 32 +/- 18 to 17 +/- 11 days/pt/yr in Groups 1 and 2 respectively, P < 0.001) whereas IA significantly decreased only in patients performing also NNV (from 1.0 +/- 0.7 to 0.2 +/- 0.3/pt/yr, P < 0.0001). Addition of NNV by pressure support modality to LTOT does not improve long term survival but significantly reduces ICU admissions and improves exercise capacity in severe COPD with hypercapnia.

Cefepime versus ceftazidime in the treatment of lower respiratory tract infections.

The objective of the study was to compare the safety and efficacy of cefepime and ceftazidime in the treatment of community acquired lower respiratory tract infections of moderate intensity. Eighty-six patients were randomized at a 2:1 ratio to receive respectively cefepime 1 g b.i.d. or ceftazidime 1 g t.i.d. The drugs were well tolerated and the occurrence of adverse events in each group was comparable. The rates of satisfactory clinical response were 96% (49/51) for cefepime and 89% (24/27) for ceftazidime. A total of 73 pathogens were isolated and pathogen eradication rates were 98% and 96% respectively for the cefepime and ceftazidime treatment groups. In conclusion, the data confirmed that cefepime could be a good alternative to ceftazidime.

MR889, a neutrophil elastase inhibitor, in patients with chronic obstructive pulmonary disease: a double-blind, randomized, placebo-controlled clinical trial.

We investigated whether MR889, a synthetic cyclic thiolic elastase inhibitor, administered for a period of 4 weeks to chronic obstructive pulmonary disease (COPD) patients, is well-tolerated, and whether it modifies biochemical indices of lung destruction. The study was a double-blind, randomized, placebo-controlled clinical trial in COPD patients. Thirty subjects were administered MR889 orally at a dose of 500 mg b.i.d. for 4 weeks, and 30 received placebo following the same schedule. In addition to safety parameters, MR889 efficacy was checked by a pretreatment/postreatment evaluation of levels of plasma elastin-derived peptides and urinary desmosine. There were no statistically significant differences between pretreatment and posttreatment efficacy parameter levels either in the control group or in the treated group. However, in a subset of treated patients with a short disease duration, the level of urinary desmosine dropped significantly with respect to pretreatment values (p = 0.004). We conclude that MR889 is safe to administer to COPD patients for a period of at least 4 weeks. During this time, MR889 does not modify biochemical markers of lung destruction in unselected COPD patients. Nevertheless, a subset of treated patients with fairly short disease duration showed a post-treatment reduction of desmosine urine levels, thus justifying the need for further studies to prove the efficacy of MR889 in modulating indices of lung destruction in COPD.

Primary lymph node invasive aspergillosis.

A case of apparently primary lymph node granulomatous aspergillosis is described. A review of the so-called primary aspergillosis cases since 1977 shows that granulomatous instead of exudative inflammation patterns have been observed in histological sections only when neither major nor minor predisposing factors have been detected in the clinical history of the patients. A possible pathogenetic role of selectively impaired cell-mediated immune response in these cases is hypothesized. Flucytosine treatment is indicated in a few selected cases of deep aspergillosis.

Acute respiratory failure, due to severe obstructive sleep apnoea syndrome, managed with nasal positive pressure ventilation.

The complications of endotracheal intubation are particularly frequent in patients with obstructive sleep apnoea syndrome (OSAS). We prospectively tested nasal ventilation in such patients admitted for acute respiratory failure. Six consecutive patients, aged 17-70 yrs, were selected for the study. All patients were confused or severely obtunded, Glasgow Coma Score (GCS) 10 (SD 2). With nasal bi-level positive airways pressure (BiPAP) all these patients improved clinical status and arterial blood gas values, avoiding intubation and invasive mechanical ventilation. The median pH increased from 7.26 (SD 0.06) to 7.36 (0.01) and to 7.43 (0.02) after, 1-3 and 24 h of nasal ventilation, respectively. Nasal ventilation lasted an average of 21 (3) h on the first day. All patients were discharged home after a median hospital stay of 28 (11) days.

Elevated serum superoxide dismutase levels correlate with disease severity and neutrophil degranulation in idiopathic pulmonary fibrosis.

1. Tissue damage in idiopathic pulmonary fibrosis is due in part to oxidant-antioxidant imbalance. 2. We evaluated the serum levels of the antioxidant enzyme Cu/Zn superoxide dismutase (EC 1.15.1.1) in 25 patients with idiopathic pulmonary fibrosis, 34 patients with sarcoidosis and 40 healthy control subjects by an enzyme immunometric assay. 3. We found that patients with idiopathic pulmonary fibrosis have higher serum Cu/Zn superoxide dismutase levels than control subjects and patients with sarcoidosis. In addition, serum Cu/Zn superoxide dismutase levels correlate with disease severity indexes in patients with idiopathic pulmonary fibrosis. 4. The increase in serum Cu/Zn superoxide dismutase level in idiopathic pulmonary fibrosis could depend on degranulation of activated neutrophils or release from damaged cells. To elucidate the contribution of neutrophil degranulation we determined the polymorphonuclear cell elastase level in the same specimens. We found a strong correlation between serum Cu/Zn superoxide dismutase and polymorphonuclear cell elastase activities, and, in patients with idiopathic pulmonary fibrosis, we observed higher levels of polymorphonuclear cell elastase than in control subjects and patients with sarcoidosis, which correlated positively with disease severity indexes. 5. Cu/Zn superoxide dismutase can catalyse the dismutation of O2 into H2O2 and generate OH.. These oxygen radicals are probably the major factors responsible for tissue damage (in particular, alveolar and endothelial cells) and fibrosis in experimental lung injury.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibodies to topoisomerase II in idiopathic pulmonary fibrosis.

Antibodies to DNA topoisomerase II (anti-topoisomerase II) were detected by ELISA in the sera of 18 out of 41 (44%) patients with idiopathic pulmonary fibrosis (IPF). Follow-up sera were also obtained from 19 of the patients. DNA topoisomerase II binding remained constantly high or low in the majority of follow-up sera, but 2 out of the 8 positive cases became negative while 3 out of the 11 negative cases became positive during follow-up. No association was found between occurrence of anti-topoisomerase II antibodies and any indices of disease severity. Furthermore, individual patient follow-up did not show any correlation between changes in topoisomerase II binding and deterioration or improvement of clinical status. In conclusion our study shows that although anti-topoisomerase II are detectable in a large fraction (approximately 50%) of IPF patients and are useful for diagnostic purposes, they do not provide a measure of clinical activity.

[The assessment of pulmonary arterial pressure by pulsed Doppler in patients with obstructive pneumopathy]. / Valutazione della pressione arteriosa polmonare mediante Doppler pulsato nei pazienti affetti da pneumopatia ostruttiva.

The severity of pulmonary arterial hypertension can be assessed by duplex-Doppler echocardiography, a subxiphoid approach and a general-purpose duplex device. Normally, the peak Doppler flow velocity occurs in midsystole and the flow profile is parabolic (bullet-like). In pulmonary arterial hypertension, changes in vascular compliance cause maximal acceleration of blood in early systole, with shortening of pulmonary acceleration time (AcT, or time to peak velocity). In the more severe cases, a midsystolic notching is visible, related to rapid deceleration of blood flow, followed by a brief secondary increase in velocity in the late systole. We studied 19 adult patients with chronic obstructive pulmonary disease with duplex-Doppler examination, with a subxiphoid approach and right heart catheterization. The study was diagnostic in all cases with Doppler recordings of good quality. An relationship was found between AcT and pulmonary mean or systolic arterial pressure at rest. An evident accurate prediction of pulmonary arterial pressure in emphysematous patients is possible by means of pulsed Doppler, also in case of low-level hypertension. We believe this method to be a simple and reliable adjunct to the non-invasive work-up of emphysematous patients and to represent a good alternative to the classical parasternal approach, which is often not feasible in these patients.

[Heart arrhythmias in chronic respiratory failure due to chronic obstructive bronchopneumopathy: the incidence and correlations with nocturnal respiratory disorders]. / Aritmie cardiache nella insufficienza respiratoria cronica da broncopneumopatia cronica ostruttiva: incidenza e correlazioni con le turbe respiratorie notturne.

The aim of this study was to assess: frequency and type of cardiac arrhythmias in patients with severe stable chronic obstructive lung disease (COLD) and chronic respiratory failure (CRF); diurnal or nocturnal predominance of the detected arrhythmias; prospective relationships between arrhythmias and nocturnal hypoxemic-hypercapnic episodes. All patients were examined with careful and complete medical history, chest roentgenogram, standard electrocardiogram, mono and bidimensional echocardiogram, respiratory function tests, arterial blood gases at rest, 24-hour dynamic electrocardiographic recording and, simultaneously, transcutaneous nocturnal monitoring of respiratory gases (TCNM). We studied 14 men: all complained of exercise-induced dyspnoea for 8 +/- 6 years; 10 of them reported usual nocturnal snoring. Respiratory function tests provided the following values (expressed in percentage compared with theoretical ones): vital capacity 58.6 +/- 15, forced expiratory volume/s 36 +/- 19, Tiffeneau index 60 +/- 19, Motley index 160 +/- 35, carbon monoxide diffusion capacity 48 +/- 26. Arterial blood gas analysis at rest resulted: PO2 47 +/- 4.5 mmHg, PCO2 49 +/- 7.9 mmHg, pH 7.38 +/- 0.3. Right ventricular diameter obtained with mono and bidimensional echocardiogram was 32 +/- 4.6 mm. Right pulmonary descending artery measured on chest roentgenogram was 23 +/- 3.8 mm. Nocturnal transcutaneous monitoring of respiratory gases showed mean PO2 of 40 +/- 9.7 mmHg and mean PCO2 of 75 +/- 19 mmHg. During night-time maximum percentage reductions of PO2 (36 +/- 17%) were measured.(ABSTRACT TRUNCATED AT 250 WORDS)

Complement activation products in idiopathic pulmonary fibrosis: relevance of fragment Ba to disease severity.

Immune complexes have been implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF), a chronic inflammatory disease of unknown etiology. Using newly developed techniques to measure complement fragments, we assessed whether complement activation occurs in IPF and its relationship to circulating immune complexes (CIC), disease severity, and prognosis. We measured the fragments C3d, C4d, and Ba of the common, classical, and alternative pathway, respectively, along with the components C3, C4, and Factor B and CIC, in 18 patients and 19 healthy subjects. The fragment to parent molecule ratios C3d/C3, C4d/C4, and Ba/Factor B were derived. Complement determinations were repeated in 14 of the patients on a second occasion separated by 8-33 months (median 17 months) from the first. All parameters were higher in patients than controls, and the difference between the two groups was significant for C3d, C4d/C4, C3, CIC (P less than 0.05) and for C4d and Ba (P less than 0.01). Fragment Ba was found to correlate with disease duration and indices of disease severity, i.e., positively with the dyspnoea score (Rs = 0.44, P less than 0.04), the physiological score (Rs = 0.50, P less than 0.02), the fibrosis score (Rs = 0.45, P less than 0.04), and a composite clinical, radiological, and physiological score (Rs = 0.48, P less than 0.03) and negatively with the forced vital capacity (Rs = -0.47, P less than 0.03). Ba was higher in those patients who deteriorated on follow-up analysis than those who improved or remained unchanged (P less than 0.04). These results show that conversion products of all complement pathways are increased in IPF and demonstrate classical pathway activation. They also show that the measurement of Ba might prove a useful laboratory test of disease severity in this condition.

Idiopathic pulmonary fibrosis: can cell mediated immunity markers predict clinical outcome?

Most of the cells found in lung parenchyma in patients with idiopathic pulmonary fibrosis are activated T lymphocytes and macrophages. The serum levels of three markers of cell mediated immunity were measured in 20 patients with idiopathic pulmonary fibrosis, in 20 normal subjects and in 12 patients with sarcoidosis to evaluate their clinical and prognostic significance in idiopathic pulmonary fibrosis. The three markers were: soluble CD8 (from activated suppressor-cytotoxic lymphocytes), soluble interleukin (IL)-2 receptors (from activated T cells and macrophages), and neopterin (from activated macrophages). Patients with idiopathic pulmonary fibrosis had higher levels of all three markers than the control subjects. Soluble IL-2 receptor and neopterin tended to be lower (though not significantly) in patients with idiopathic pulmonary fibrosis than in those with sarcoidosis, whereas soluble CD8 was similar in the two groups of patients. No correlation was found between soluble IL-2 receptors or soluble CD8 and the clinical, radiological, and physiological measures of disease activity or with clinical outcome (after a mean follow up of 23 months). Tumour necrosis factor levels were also determined. Only 30% of patients with idiopathic pulmonary fibrosis or sarcoidosis had detectable circulating tumour necrosis factor; these patients had a lower percentage of bronchoalveolar lavage fluid neutrophils in their lavage fluid. Tumour necrosis factor levels did not correlate with clinical measures of severity or outcome. Thus our data support the hypothesis that cell mediated alveolitis occurs in idiopathic pulmonary fibrosis. They do not, however, provide evidence to support the use of these markers of cell mediated immunity to monitor the clinical course in these patients.

Autoantibodies to DNA topoisomerase II in cryptogenic fibrosing alveolitis and connective tissue disease.

Sera from patients with autoimmune lung and connective tissue diseases were investigated for antibodies to topoisomerase II. Anti-topoisomerase II antibodies were detected by ELISA in 37% of sera from patients with cryptogenic fibrosing alveolitis (CFA), in one (8%) case of sarcoidosis and in 31% of sera from systemic lupus erythematosus (SLE) patients. Sera from rheumatoid arthritis, juvenile rheumatoid arthritis, progressive systemic sclerosis, Sjögren's syndrome and undifferentiated connective tissue disease were negative. CFA and sarcoidosis sera strongly reacted in immunoblotting with a 170 kD protein, also recognized by rabbit antiserum to recombinant topoisomerase II, while SLE sera presented a weak reaction. Pre-adsorption with dsDNA dramatically decreased the topoisomerase II binding in ELISA by the most positive SLE serum, but did not affect the binding by the most positive CFA serum, thus indicating that anti-topoisomerase II reactivity of SLE sera is probably due either to cross-reacting antibodies or, in part, to minor DNA contamination of our enzyme preparation. The determination of DNA topoisomerase II relaxation activity, performed after incubation with antibody-positive sera, showed that only CFA sera precipitate enzymatic activity. The finding that CFA presents antibodies to an enzyme essential to cell survival stresses the role of autoimmunity in the pathogenesis of idiopathic pulmonary fibrosis. This may offer further insight into the cause of autoimmune disease and prove a valuable tool in the study of enzyme molecular biology.

[Pulmonary eosinophilic granuloma in adults. Case histories and a review of the literature]. / Il granuloma eosinofilo polmonare dell'adulto. Contributo casistico e revisione della letteratura.

Histiocytosis X is a disease of unknown origin which usually affects multiple organs, including the lung. The age of onset, the clinical course and the pattern of spread allow a distinction to be made between 3 varieties: Letterer-Siwe, Hand-Schüller-Christian and eosinophilic granuloma. The latter form, in adult patients, may predominantly or solely affect the lungs. The authors reviewed clinical, radiographic and CT findings of 7 adult patients with pulmonary eosinophilic granuloma, picked out of a series of 265 cases of interstitial lung pathology, diagnosed since 1973. Typical pulmonary involvement is bilateral, symmetrical and predominates in the upper areas. Honeycomb pattern was found in 1 patient at the onset of symptoms, and in 2 cases during the follow-up, without severe reduction in pulmonary volumes. Pneumothorax was observed in 3 cases and bone lesions in 2. CT added new and important informations such as presence, size and wall thickness of "cystic" lesions. New laboratory tests and bronchoalveolar lavage demonstrated minor diagnostic usefulness than radiological findings. The authors conclude by discussing such problems as prognostic factors and differential diagnosis.

Failure of automatic control of ventilation (Ondine's curse) associated with viral encephalitis of the brainstem: a clinicopathologic study of one case.

A case of Ondine's curse associated with hypothalamic dysfunction in an 8-year-old boy is described. The neuropathological examination revealed a viral encephalitis affecting the hypothalamus and the brainstem. In the medulla the inflammatory process involved the reticular formation and the nuclei considered to control automatic respiration such as the dorsal motor nucleus of the vagus, the nucleus tractus solitarii and the nucleus ambiguous. Although Ondine's curse following viral infection of the central nervous system has been previously reported this represents the first case of viral encephalitis to be pathologically documentated.

Sleep-related breathing impairment in myotonic dystrophy.

Respiratory failure has been described in myotonic dystrophy; it worsens during sleep but its central or peripheral origin has yet to be determined. Moreover, patients may present severely disturbed sleep and daytime somnolence. Eight patients with mild to moderate myotonic dystrophy were studied to assess breathing function while awake and during sleep by means of the pulmonary function tests, nocturnal polysomnographic examination and the multiple sleep latency test (MSLT). Three patients had restrictive respiratory defects; none had signs of airway obstruction. All patients had very disrupted nocturnal sleep. Of six patients who underwent the MSLT only two showed a mild tendency to sleep during the day. Six patients had pathological apnoea plus hypopnoea index [(A+H)I] and there was a prevalence of central apnoeas. The apnoeas occurred while resting but awake and throughout all sleep stages. Only two patients (the ones with the least vital capacity) had episodes of progressive oxygen desaturation during rapid eye movement sleep, similar to those found in other restrictive disorders and in chronic obstructive pulmonary disease. It is concluded that the breathing pattern characteristic of our myotonic dystrophy patients was the occurrence of central apnoeas both at rest while awake and during sleep.