Marco Confalonieri

Macitentan for the treatment of idiopathic pulmonary fibrosis: the randomised controlled MUSIC trial

Idiopathic pulmonary fibrosis is a progressive, fatal disease. This prospective, randomised, double-blind, multicentre, parallel-group, placebo-controlled phase II trial (NCT00903331) investigated the efficacy and safety of the endothelin receptor antagonist macitentan in idiopathic pulmonary fibrosis. Eligible subjects were adults with idiopathic pulmonary fibrosis of <3 years duration and a histological pattern of usual interstitial pneumonia on surgical lung biopsy. The primary objective was to demonstrate that macitentan (10 mg once daily) positively affected forced vital capacity versus placebo. Using a centralised system, 178 subjects were randomised (2:1) to macitentan (n=119) or placebo (n=59). The median change from baseline up to month 12 in forced vital capacity was -0.20 L in the macitentan arm and -0.20 L in the placebo arm. Overall, no differences between treatments were observed in pulmonary function tests or time to disease worsening or death. Median exposures to macitentan and placebo were 14.5 months and 15.0 months, respectively. Alanine and/or aspartate aminotransferase elevations over three times upper limit of normal arose in 3.4% of macitentan-treated subjects and 5.1% of placebo recipients. In conclusion, the primary objective was not met. Long-term exposure to macitentan was well tolerated with a similar, low incidence of elevated hepatic aminotransferases in each treatment group. Long-term exposure to macitentan was well tolerated in IPF in a trial that did not meet its primary end-point http://ow.ly/p0RDL

Noninvasive mechanical ventilation improves the immediate and long-term outcome of COPD patients with acute respiratory failure

Noninvasive positive pressure ventilation (NPPV) has been proposed in COPD patients with acute on chronic respiratory failure (ACRF) in order to avoid endotracheal intubation and to improve immediate outcome, but long-term outcome of this therapeutic approach is still undefined. We evaluated short- and long-term (1 year) outcome of early administration of NPPV in 24 patients with ACRF due to exacerbated COPD (Group A) in comparison with 24 matched historical-control patients treated conventionally (Group B). Patients of Group A were initially treated with NPPV via nasal mask in the presence of pH < or = 7.32, and/or Pa,O2 < 7.98 kPa, and/or Pa,CO2 > 7.18 kPa, plus signs of respiratory distress. In-hospital survival rate was not significantly different in Group A vs Group B, but the patients treated with NPPV showed an earlier improvement in blood gases and a better pH and respiratory rate at discharge. Only 2 patients of Group A needed endotracheal intubation as compared with 9 of Group B. Hospital stay was significantly reduced in survivors of Group A vs Group B. Further severe relapses of ACRF in Group A were treated using NPPV. The number and length of further hospitalizations for pulmonary exacerbations were significantly higher in Group B compared with Group A. The survival rate at 12 months was significantly lower in Group B than in Group A (50% vs 71%). In conclusion, NPPV administration in patients with ACRF due to exacerbated COPD improves not only immediate but also long-term outcome.

Noninvasive ventilation for treating acute respiratory failure in AIDS patients with Pneumocystis carinii pneumonia

Objective. To compare noninvasive positive pressure ventilation (NPPV) vs. invasive mechanical ventilation in AIDS patients with Pneumocystis carinii pneumonia (PCP)-related acute respiratory failure (ARF).Design: A single-center, prospective, case-control trial.Setting: An ICU of a private tertiary hospital specialized in infectious disease.Patients: Forty-eight AIDS patients with severe PCP-related ARF needing mechanical ventilation.Interventions: Twenty-four patients treated with NPPV by a facial mask strictly matched with 24 patients treated with invasive ventilation by endotracheal intubation.Results: Use of NPPV avoided intubation in 67% of patients, and avoidance of intubation was associated with improved survival (100% vs. 38%; P=0.003). NPPV-treated patients required fewer invasive devices (P<0.001) and had a lower incidence of pneumothoraces (8.3% vs. 37.5%; P=0.039). The NPPV-treated group required a nurse workload similar to that of the conventional ventilation group, but this group had a shorter duration of stay in the ICU (P=0.013). The NPPV-treated group had a lower mortality in the ICU, the hospital and within 2 months of study entry. Differences in mortality between the two groups disappeared after 6 months.Conclusions: The findings of this study seem to provide further support for applying NPPV in AIDS patients with severe PCP-related ARF as a first-line therapeutic choice, but randomized controlled trials are required to confirm our results.

Metabolic exercise test data combined with cardiac and kidney indexes, the MECKI score: A multiparametric approach to heart failure prognosis

OBJECTIVES We built and validated a new heart failure (HF) prognostic model which integrates cardiopulmonary exercise test (CPET) parameters with easy-to-obtain clinical, laboratory, and echocardiographic variables. BACKGROUND HF prognostication is a challenging medical judgment, constrained by a magnitude of uncertainty. METHODS Our risk model was derived from a cohort of 2716 systolic HF patients followed in 13 Italian centers. Median follow up was 1041days (range 4-5185). Cox proportional hazard regression analysis with stepwise selection of variables was used, followed by cross-validation procedure. The study end-point was a composite of cardiovascular death and urgent heart transplant. RESULTS Six variables (hemoglobin, Na(+), kidney function by means of MDRD, left ventricle ejection fraction [echocardiography], peak oxygen consumption [% pred] and VE/VCO2 slope) out of the several evaluated resulted independently related to prognosis. A score was built from Metabolic Exercise Cardiac Kidney Indexes, the MECKI score, which identified the risk of study end-point with AUC values of 0.804 (0.754-0.852) at 1year, 0.789 (0.750-0.828) at 2years, 0.762 (0.726-0.799) at 3years and 0.760 (0.724-0.796) at 4years. CONCLUSIONS This is the first large-scale multicenter study where a prognostic score, the MECKI score, has been built for systolic HF patients considering CPET data combined with clinical, laboratory and echocardiographic measurements. In the present population, the MECKI score has been successfully validated, performing very high AUC.

Respiratory intensive care units in Italy: a national census and prospective cohort study

BACKGROUND In Italy, respiratory intensive care units (RICUs) provide an intermediate level of care between the intensive care unit (ICU) and the general ward for patients with single organ respiratory failure. Because of the lack of official epidemiological data in these units, a two phase study was performed with the aim of describing the work profile in Italian RICUs. METHODS A national survey of RICUs was conducted from January to March 1997 using a questionnaire which comprised over 30 items regarding location, models of service provision, staff, and equipment. The following criteria were necessary for inclusion of a unit in the survey: (1) a nurse to patient ratio ranging from 1:2.5 to 1:4 per shift; (2) availability of adequate continuous non-invasive monitoring; (3) expertise for non-invasive ventilation (NIV) and for intubation in case of NIV failure; (4) physician availability 24 hours a day. Between November 1997 and January 1998 a 3 month prospective cohort study was performed to survey the patient population admitted to the RICUs. RESULTS Twenty six RICUs were included in the study: four were located in rehabilitation centres and 22 in general hospitals. In most, the reported nurse to patient ratio ranged from 1:2 to 1:3, with 36% of units reporting a ratio of 1:4 per shift. During the study period 756 consecutive patients of mean (SD) age 68 (12) years were admitted to the 26 RICUs. The highest proportion (47%) were admitted from emergency departments, 19% from other medical wards, 18% were transferred from the ICU, 13% from specialist respiratory wards, and 2% were transferred following surgery. All but 32 had respiratory failure on admission. The reasons for admission to the RICU were: monitoring for expected clinical instability (n=221), mechanical ventilation (n=473), and weaning (n=59); 586 patients needed mechanical ventilation during their stay in the RICU, 425 were treated with non-invasive techniques as a first line of treatment (374 by non-invasive positive pressure, 51 by iron lung), and 161 underwent invasive mechanical ventilation (63 intubated, 98 tracheostomies). All but 48 patients had chronic respiratory disease, mainly chronic obstructive pulmonary disease (COPD; n=451). More than 70% of patients (n=228) had comorbidity, mainly consisting of heart disorders. The median APACHE II score was 18 (range 1–43). The predicted inpatient mortality risk rate according to the APACHE II equation was 22.1% while the actual inpatient mortality rate was 16%. The mean length of stay in the RICU was 12 (11) days. The outcome in most patients (79.2%) admitted to RICUs was favourable. CONCLUSIONS Italian RICUs are specialised units mainly devoted to the monitoring and treatment of acute on chronic respiratory failure by non-invasive ventilation, but also to weaning from invasive mechanical ventilation. The results of this study provide a useful insight into an increasingly important field of respiratory medicine.

Intermediate respiratory intensive care units in Europe: a European perspective

In the early 1950s an outbreak of poliomyelitis in Scandinavia highlighted for the first time the need for hospital units specialised in treating episodes of acute respiratory failure. The first intensive care units (ICUs), at that time utilising non-invasive techniques such as tank ventilators, were therefore built in Northern Europe. Later on positive pressure ventilation via an endotracheal tube or a tracheotomy became common and the modalities of non-invasive ventilation were progressively abandoned.1 Insertion of an endotracheal tube is usually performed after sedation and paralysis of the patient, and for this reason for many years mechanical ventilation was the exclusive field of anaesthetists so that in many European countries ICUs are still run mainly by anaesthetists rather than “organ specialists”. This clinical and management background has also conditioned respiratory medicine in Europe, and only a few European countries include specific training in emergency medicine and mechanical ventilation as part of the programme of the specialisation in respiratory medicine.2 This is not the case in North America where intensive care medicine has been closely linked to respiratory medicine for many years. In the middle of the 1960s, following the pioneering experience of Dr Petty,3 a growing number of specialised respiratory intensive care units (RICUs) started to spread all over the USA alongside, and not in competition with, “general” ICUs.4 The RICUs were designed to treat acute or acute-on-chronic respiratory failure due to any pulmonary disease with monitoring systems equal to those of the ICUs. These units necessitated a specialised environment and personnel, with increasing costs, so that in the 1980s a new class of “step down” or “intermediate” critical care units, the so-called non-invasive respiratory care units (NRCU) or high dependency units (HDU)5 were developed as a less costly option for patients receiving long term mechanical …

Severe exacerbations of chronic obstructive pulmonary disease treated with BiPAP by nasal mask.

Bi-level pressure support ventilation via a nasal mask (NIPSV) was provided to 28 consecutive unselected patients with acute respiratory failure due to exacerbation of chronic obstructive pulmonary failure (COPD). If NIPSV improved gas exchange within 2 h, it was continued. Otherwise, patients would be promptly intubated. The patients median age was 68 years (minimum 56, maximum 82). The arterial blood gas drawn before initiating NIPSV showed (FiO2 21%) a mean PaO2 of 41.3 +/- 6 mm Hg, a mean PaCO2 of 66 +/- 15 mm Hg and a mean pH of 7.31. Upon admission the mean respiratory rate was 36 breaths/min and the median Apache II score was 20.5 (minimum 13, maximum 32). Despite oxygen administration all patients failed to improve their PaO2 and/or showed a consistent and dangerous hypercapnic response. NIPSV was performed with a median inspiratory positive airway pressure of 14 cm H2O (minimum 10, maximum 20) and a median expiratory positive airway pressure of 4 cm H2O (minimum 3, maximum 6). Eighteen patients (64%) were successfully ventilated with NIPSV, while in 10 (36%) NIPSV failed. A high Apache II score, but not admission blood gas exchange or respiratory rate, seems to be correlated with the failure to ventilate with NIPSV. The results of our preliminary experience suggest the use of NIPSV as an initial approach to acute respiratory failure due to exacerbation of COPD, particularly in patients with an Apache II score of less than 29.

Efficacy of pirfenidone for idiopathic pulmonary fibrosis: An Italian real life study

BACKGROUND In this retrospective Italian study, which involved all major national interstitial lung diseases centers, we evaluated the effect of pirfenidone on disease progression in patients with IPF. METHODS We retrospectively studied 128 patients diagnosed with mild, moderate or severe IPF, and the decline in lung function monitored during the one-year treatment with pirfenidone was compared with the decline measured during the one-year pre-treatment period. RESULTS At baseline (first pirfenidone prescription), the mean percentage forced vital capacity (FVC) was 75% (35-143%) of predicted, and the mean percentage diffuse lung capacity (DLCO) was 47% (17-120%) of predicted. Forty-eight patients (37.5%) had mild disease (GAP index stage I), 64 patients (50%) had moderate IPF (stage II), and 8 patients (6.3%) had severe disease (stage III). In the whole population, pirfenidone attenuated the decline in FVC (p = 0.065), but did not influence the decline in DLCO (p = 0.355) in comparison to the pre-treatment period. Stratification of patients into mild and severe disease groups based on %FVC level at baseline (>75% and ≤75%) revealed that attenuation of decline in FVC (p = 0.002) was more pronounced in second group of patients. Stratification of patients according to GAP index at baseline (stage I vs. II/III) also revealed that attenuation of decline in lung function was more pronounced in patients with more severe disease. CONCLUSIONS In this national experience, pirfenidone reduced the rate of annual FVC decline (p = 0.065). Since pirfenidone provided significant treatment benefit for patients with moderate-severe disease, our results suggest that the drug may also be effective in patients with more advanced disease.

High-frequency percussive ventilation improves perioperatively clinical evolution in pulmonary resection.

Objective:During thoracotomy, positive end-expiratory pressure is applied to the dependent lung and continuous positive airway pressure (CPAP) inflates the nondependent lung to avoid hypoxemia. These methods do not allow the removal of produced secretions. We hypothesized that high-frequency percussive ventilation (HFPV) can improve both conditions and reduce hospital length of stay in these patients. Design:Randomized prospective study. Setting:University Hospital. Patients:Fifty-three consecutive patients undergoing elective pulmonary partial resection were enrolled. Nine were excluded because of surgical reasons. Interventions:The nondependent lung was ventilated with HFPV in 22 patients and other 22 received CPAP. In both groups, the dependent lung was ventilated with continuous mechanical ventilation. Measurement and Main Results:Cardiocirculatory variables and blood gas analysis were measured during surgery. Postoperatively, all patients underwent chest physiotherapy, and Spo2, body temperature, the amount of sputum produced, and chest radiography were recorded. Before nondependent lung re-expansion, HFPV patients presented higher Pao2 than CPAP group (p = 0.020). The amount of secretions was higher in chronic obstructive pulmonary disease patients treated with HFPV than in those who received CPAP (199 and 64 mL, respectively, p = 0.028). HFPV increased by 5.28 times the chance of sputum production by chronic obstructive pulmonary disease patients (&khgr;2 = 46.66, p < 0.0001; odds ratio = 5.28). A patient treated with HFPV had a 3.14-fold larger chance of being discharged earlier than a CPAP-treated subject (likelihood ratio = 11.5, p = 0.0007). Conclusions:Under the present settings, HFPV improved oxygenation in one-lung ventilation during pulmonary resection. Postoperatively, it decreased the length of stay and increased the removal of secretions in comparison with CPAP.

Haemodynamic response during initiation of non-invasive positive pressure ventilation in COPD patients with acute ventilatory failure

The aim of this study was to check non-invasively the acute haemodynamic effects of non-invasive positive pressure ventilation (NPPV) initiation in patients with chronic obstructive pulmonary disease (COPD) and acute ventilatory failure (AVF). Nineteen consecutive COPD patients with AVF were evaluated clinically and echocardiographically during spontaneous breathing with O2 supplementation and during NPPV plus O2. NPPV was administered with a scheduled inspiratory pressure of 15 cmH2O and an expiratory pressure of 4 cmH2O, via facial mask. Arterial blood gas improved significantly (pH and PaCO2; P < 0.001) during NPPV administration in all patients; none had hypotension or acute arrhythmia. Doppler echocardiographic evaluation was feasible in most of the patients (16/18). With reference to baseline values, no significant changes in pulmonary artery pressures and cardiac output (CO) were observed by Doppler echocardiography in most patients. Only four patients (21%) showed a significant reduction (> 15%) of CO during NPPV. No correlation was found between decreased CO and baseline data, but three patients showing CO reduction had poor tolerance to mask ventilation and did not improve respiratory rate during NPPV. It was concluded that the initiation of NPPV by facial mask does not alter haemodynamics acutely in most COPD patients with AVF, but individual patients may experience reduction in CO in spite of adequate oxygen saturation levels. This suggests that caution should be used when applying pre-determined and fixed pressures during NPPV. Monitoring haemodynamics by Doppler echocardiography may be useful for early detection of haemodynamic alterations due to NPPV application in patients with AVF.