Mrinal Sircar and Mark Elliott

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An exacerbation of chronic obstructive pulmonary disease (COPD) of sufficient severity to necessitate hospital admission indicates a poor prognosis, carrying a 6-26% mortality [1,2]. In one study, an 11% in-hospital mortality was reported, but this increased over the next 2months, 6months, lyear and 2 years of follow-up to 20%, 33%, 43% and 49%, respectively [3]. Another study found 5-year survival rates of 45% after hospital discharge, but this decreased to 28% with any further episode of hospitalization [4]. Numerous studies have been carried out to identify predictors of mortality during an acute exacerbation of COPD. It has variously been correlated to: age, alveolar-arterial oxygen gradient greater than 5.5 kPa (41 mmHg), ventricular or atrial arrhythmias [4,5], requirement for long-term oxygen therapy, low albumin or sodium, low forced expiratory volume in 1s (FEV1) [4,6] and reversibility of hypercapnia [7]. Mortality increases with low body mass index [8] and in the presence of comorbidity, such as other organ failure [9]. The most important predictor of in-hospital mortality [2,10,11] and need for intubation [12] is the level of acidosis. Unsurprisingly, patients admitted to the intensive-care unit (ICU) have a high mortality, for instance Seneff et al. [13] reported overall hospital mortality at 24% following admission to the ICU, doubling to 59% at 1year. Others have reported lower mortality rates after admission to ICU for mechanical ventilation, the ICU and hospital case fatality rates in one study being 1% and 11%, respectively [14]. On the other hand, mortality as high as 88.8% at 2 years after ICU admission has also been reported [15].

Non-invasive ventilation

Following a number of case series of the successful use of non-invasive mechanical ventilation (NIMV) [16-18] in patients with an acute exacerbation of COPD, there has been a great expansion of interest in this area. The obvious attraction of NIMV is the avoidance of intubation and its attendant complications. Patients do not require sedation and can cooperate with physiotherapy and eat normally [19]. Intermittent ventilatory support is practical, and patients can undergo mobilization at an early stage. Furthermore, patients can communicate with medical and nursing staff and with family; this is likely to reduce the feelings of powerlessness and anxiety [13]. However, concerns have been raised that when NIMV is unsuccessful, the delay in intubation may affect the outcome [20,21], that a nasal or face mask is uncomfortable and claustrophobic and that the procedure is more time-consuming for medical and nursing staff [22].

Physiologically, NIMV is little different from invasive mechanical ventilation; positive pressure is delivered to the lungs, but because of difficulties in getting a perfect seal with the mask, it is theoretically less efficient than invasive ventilation. On the other hand, the fact that NIMV is relatively less efficient may be to its advantage. Barotrauma such as pneumothorax is not uncommon with ventilation after intubation, but it has not been reported in any of the major studies of NIMV, perhaps due to the lack of a perfect seal acting as a safety valve preventing high pressures being transmitted to the lungs. NIMV decreases inspiratory muscle effort and respiratory rate and increases tidal volumes and oxygen saturation in stable COPD patients [23] and during an acute exacerbation [24]. Arterial PaO2 increases while the PaCO2 decreases with NIMV [17,25]. In a study by Celikel et al., NIMV significantly improved PaO2, PaCO2, pH and respiratory rate, while medical treatment achieved only an improvement in respiratory rate [26]. For the same FiO2, the AaDO2 increases due to a rise in clearance of CO2 and hence increased respiratory exchange ratio [25]. There is a fall in cardiac output leading to a slight decrease in systemic oxygen delivery, but this is not accompanied by a change in PvO2. There appears to be no improvement in VA/Q ratio with NIMV [25].

Ventilators usually used for NIMV are either volume-targeted or pressure-targeted. There are theoretical advantages to each mode, but broadly speaking they are comparable in efficacy. Volume-targeted ventilators have been shown to produce more complete off-loading of the respiratory muscles, but at the expense of comfort [27]. In intubated patients however, assist pressure controlled ventilation has been shown to be more effective than assist control volume ventilation at reducing various parameters of respiratory muscle effort, although this difference was only seen at moderate tidal volumes and low flow rates [28]. In stable patients, little difference in gas exchange was seen with different types of ventilator [23,29]. In terms of outcome, Vitacca et al. [30] found that there was no difference whether volume-targeted or pressure-targeted machines were used, but pressure-targeted machines were better tolerated by patients. A new mode of proportional assisted ventilation (PAV) improves gas exchange and dyspnoea in stable COPD [31] and has been used successfully in the treatment of acute respiratory failure of various aetiologies [32]. PAV delivers ventilation according to patient demand, which should theoretically be more comfortable, but makes the assumption that the patient with respiratory failure knows best what he or she needs in terms of ventilatory support. PAV using flow assistance and positive end-expiratory pressure (PEEP) achieved greatest improvement in minute ventilation, dypnoea and reduction in pressure-time product per breath of the respiratory muscles and diaphragm in COPD patients with acute respiratory failure [33]. It has been shown to decrease patient effort, work of breathing and neuromuscular drive (P0.1) in COPD patients being weaned off invasive mechanical ventilation [34,35]. Further data are needed comparing PAV with conventional modes of ventilation.

PEEP can be added during NIMV and has beneficial effects, off-loading the respiratory muscles, probably by counterbalancing the inspiratory threshold load imposed by intrinsic PEEP [36] and lavaging carbon dioxide from the mask [37]. In a short-term study in stable patients, the addition of PEEP has been shown to reduce oxygen delivery despite an adequate SaO2 [38]. Mask continuous positive airway pressure (CPAP) has also been shown to significantly decrease respiratory rate and the subjective sensation of dyspnoea, decreasing PaCO2, increasing PaO2 [39], significantly improving ventilation [40] and avoiding intubation and mechanical ventilation [41] in exacerbations of COPD. In stable patients, the degree of unloading with CPAP is less than with NIMV [23], but given the lack of randomized controlled data on the use of CPAP in acute exacerbations of COPD, in contrast to NIMV (see below), its use should be confined to centres in which NIMV is not available.

What is the evidence for the clinical usefulness of non-invasive ventilation?

Numerous uncontrolled studies have reported efficacy of NIMV in acute exacerbations of COPD, producing clinical and physiological improvement. Meduri et al. [16] successfully ventilated 10 patients, including six with exacerbations of COPD, using a pressure-control mode delivered through a face mask in 1989 and followed up subsequently with a larger series of 18 patients with hypercapnic respiratory failure, with similar results [42]. Similar results have also been reported by other workers in uncontrolled studies [18,43-47]. However, in a small study, including only three patients with COPD, NIMV was not found to be useful and indeed took up a considerable amount of nursing time [22]. The duration of NIMV required may be brief, suggesting that even short periods of successful ventilation may be sufficient to buy time for other therapies to work. Hilbert et al. [48] found that, using sequential mask bilevel positive airway pressure support, at least 30 min every 3 hours, only 11 patients, compared to 30 of 42 matched historical controls, eventually re quired intubation. In-hospital mortality was similar, but duration of ventilatory support and length of ICU stay were shortened.

There have been a number of other studies comparing NIMV with historical controls. Brochard et al. [17] reported 13 patients, of whom 12 could be managed with face mask NIMV without requiring intubation. These patients were also weaned off their ventilator faster and spent less time on the intensive-care unit than the controls. In another study, 24 patients treated with NIMV showed more rapid improvement in blood gases and a better pH and respiratory rate at discharge as compared to matched historical controls [49]. Only two patients receiving NIMV required intubation, compared with nine controls. Hospital stays were also shorter in the survivors in the NIMV group, but the in-hospital survival rates were no different. However, long-term survival at 12months was significantly better in the patients receiving NIMV (71% vs. 50%). Vitacca et al. [50] also found no difference in hospital mortality in patients receiving NIMV compared to historical controls who were intubated and ventilated (20% vs. 26%), but a survival advantage with NIMV became apparent at 3months (77% vs. 52%) and 12months (70% vs. 37%).

This longer-term survival advantage with NIMV is intriguing. It has been suggested that it is due to imperfect matching of the control and patient groups [51]. However, there are other possible explanations. If ICU care has been prolonged, and weaning difficult, there may be reluctance on the part of either medical staff or the patients themselves to consider invasive mechanical ventilation (IMV) for a subsequent exacerbation. Secondly, it is possible that IMV has adverse effects that may be significant later; electrophysiological and biopsy evidence of muscle dysfunction has been shown after as little as 1 week of invasive ventilation [52,53]. Such dysfunction of the respiratory muscles will reduce the capacity of the respiratory muscle pump, which may increase the risk of ventilatory failure in subsequent exacerbation. However, these observations are speculative and need to be substantiated in further prospective studies.

The first prospective randomized controlled trial of NIMV in COPD exacerbation was reported in 1993 [54] (Table 16.1). Patients receiving standard medical therapy and NIMV from a volume-cycled ventilator in the assisted control mode had a significantly greater improvement in both the pH and PaCO2 as compared to patients on standard medical therapy alone. On an intention-to-treat basis, there was no difference in survival between NIMV and conventional therapy, but only one out of 26 patients who actually received NIMV died, compared to nine out of 30 patients in the control group (P = 0.014). However, the mortality in the control arm was higher than expected from other studies, given that the mean pH at the time of randomization showed only mild acidosis, and in addition few patients who died were offered IMV. In a multicentre study in five European ICUs, Brochard et al. [55]

Table 16.1 Randomized controlled trials of non-invasive mechanical ventilation in acute exacerbations of chronic obstructive pulmonary disease.


Location for trial

No. of patients (study/control)

Type of ventilator

Baseline pH (NIMV/control)


(NIMV vs. control)


Bott 1993



Volume-cycled ventilation via nasal mask


Mortality 1/26 vs. 9/30 ETI0/26 vs. 2/30 + 3 NIMV

NIMV + ST vs. ST alone

Kramer 1995

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