Interpretation of main findings

We included in the review 17 randomised controlled trials (RCTs) involving 1264 participants. This represents a substantial increase from the original review in the number of studies and number of participants included. Trial results demonstrate clear benefits associated with use of NIV as adjunctive therapy to usual care (compared with usual care alone) for treatment of patients admitted to hospital with acute hypercapnic respiratory failure (AHRF) secondary to acute exacerbation of COPD (AECOPD). Benefits were consistent across a range of outcomes considered to be clinically important. Compared with usual care, the overall pooled effect of NIV across included studies included significant reductions in risk of mortality and need for endotracheal intubation, with the average number of patients required to be treated to derive benefit in the magnitude of 12 and 5, respectively. Although no clinical consensus has been reached regarding the most acceptable number needed to treat for an additional beneficial outcome (NNTB) for such outcomes, this approach appears to represent good return upon investment with respect to the importance of these clinical outcomes and the generally low incidence of adverse events reported in studies included in this review. Effects of NIV + usual care versus usual care alone across secondary outcomes were derived from a significantly smaller pool than derived across primary outcomes and were less consistent. The magnitude of effect observed among subgroups defined on the basis of admission pH (< 7.30 or from 7.35 to 7.30) or clinical setting (ICU vs ward) did not significantly differ for most outcomes, with the exception of hospital length of stay, which demonstrated significantly greater benefit for those with more severe acidosis (pH < 7.30) than for those with milder acidosis (pH 7.35 to 7.30). This suggests that benefits derived from NIV use are likely to extend across a range of differing clinical scenarios.

Researchers have reported a significant 46% relative reduction in risk of mortality with NIV compared with usual care. This equates to potential avoidance of one death for every 12 patients treated with NIV (a slight increase from the original review (NNTB = 10)). This mortality benefit across the large number of included studies is of considerable clinical importance. Debate has surrounded the issue of whether NIV would delay necessary endotracheal intubation and therefore increase mortality. However, this position is not supported by the findings of this review. Mortality with NIV was reduced overall and across almost all of the pH and location subgroups, inferring generally similar responses irrespective of such factors. The only subgroup that did not reach statistical significance for this outcome was the ICU subgroup (risk ratio (RR) 0.60, 95% confidence interval (CI) 0.34 to 1.07). It is noteworthy to mention that this subgroup included the Khilnani 2010 study, which was unique compared with any other included study, as the mean admission partial pressure of carbon dioxide (PaCO₂) across both groups was in excess of 80 mmHg. This would be considered an indicator for intubation at many hospitals. Although this study demonstrated significant improvement in arterial blood gases and need for intubation, the mortality effect was small and non‐significant (two deaths in NIV group due to septicaemia and acute coronary event vs one death in the control group due to septicaemia). In translating findings related to this outcome into clinical practice, it may be worth considering that the potential for mortality in clinical practice could be greater than that observed in clinical trials owing to factors related to patient suitability for mechanical ventilation. Individuals who are poor candidates for intubation and ventilation, including those with a very poor prognosis or a low likelihood of satisfactory quality of life or prespecified end‐of‐life choices (e.g. not for resuscitation/intubation wishes), are unlikely to feature in clinical trials such as those included within this review, yet may be appropriate candidates for NIV.

Need for endotracheal intubation was reduced by approximately two‐thirds (64%) relative to usual care, equating to just five patients needing to be treated with NIV to potentially avoid intubation of one patient. The magnitude of benefit was clear and statistically significant for all subgroups, and no significant differences were observed for this outcome across subgroups related to admission pH or treatment location. These data further demonstrate the clearly important clinical benefits associated with NIV. It is worth noting that findings related to this outcome could be considered a conservative underestimation of the true effect of NIV due to inherent challenges in evaluating and reporting this outcome in clinical trials. Whereas failure of treatment for patients enrolled into an NIV treatment arm commonly results in progression to intubation and mechanical ventilation or withdrawal of treatment, failure in a usual care arm typically results in escalation of medical management to 'off‐protocol' NIV, followed by potential subsequent intubation and mechanical ventilation (or treatment withdrawal). The precise incidence of 'actual intubation' therefore is likely to be less than the 'need for intubation' in usual care groups. Additionally, actual intubation rates may be influenced by the availability of beds in ICU settings. Therefore we considered the need for intubation as our principal definition for this outcome, as we believed this more accurately evaluated treatment 'success' versus 'failure'. Studies that reported only actual intubation rates were not rated as having high risk of bias due to data contamination, as we believed this phenomenon was representative of clinical care and was unlikely to overinflate effect estimates related to this outcome.

Need for endotracheal intubation is not always considered a 'negative' outcome, particularly in the context of treatment failure and concerns regarding the timeliness of 'essential' intubation and mechanical ventilation. Although this review did not set out to answer specific questions related to such examples, some inferences may be drawn from the present data (with due caution related to indirectness of the data for answering such questions) on the basis of lack of significant differences in beneficial effect estimates for the need for intubation (and mortality) in subgroups defined according to baseline pH levels. Although time to intubation was not specifically examined within this review, the data should alleviate some concerns regarding the safety of NIV as a first‐line therapy option (or trial of therapy for some) for patients who may present later in the course of their AHRF (when concerns regarding timeliness of invasive ventilation may be greater).

NIV use was not associated with exclusively positive outcomes. Data from our review demonstrate the need for intubation criteria was met by 66 of the 559 participants in the intervention group (12% incidence; Analysis 1.2). Rapid access to teams and resources capable of delivering invasive ventilation would therefore appear advisable for individuals considered appropriate for escalation of care when NIV is used. However, it is essential that evaluations and judgements regarding end‐of‐life decisions are made for all patients with severe AECOPDs characterised by AHRF on an individual needs basis. Although some patients with COPD may not be candidates for invasive ventilation, a considerable proportion of those who present to hospital with severe exacerbations requiring NIV have greater underlying disease severity and, in the setting of NIV treatment failure, may be more appropriate for attempted continuation/titration of NIV, conservative management, or treatment withdrawal. For example, patients who may have received prolonged (> 7 days) intubation/ventilation in the past owing to respiratory muscle atrophy may be characterised by reduced ventilatory reserve and impaired capacity to clear pulmonary secretions ‐ features that are likely to recur during subsequent exacerbations (Coakley 1992, Helliwell 1991; Le Bourdelles 1994). Other risks associated with invasive positive pressure ventilation such as barotrauma, cardiac output impairment, increased work of breathing related to dead space ventilation (due to length of the endotracheal tube), and the potential for prolonged or difficult weaning (Shapiro 1986) are relevant factors for consideration when treatment plans for such patients are determined.

The findings of this review are intended to be interpreted with respect to initial management of AHRF secondary to AECOPD. Several studies have been conducted to examine the effectiveness of NIV in patients who are weaning from invasive ventilation; we explicitly excluded these from this review and believe that our results should not be extrapolated to such contexts.

It is noteworthy to reflect upon Barbe 1996, which was one of the only studies to conclude that addition of NIV to usual care was not beneficial. This trial adopted a less common approach to delivery of NIV, as investigators delayed initiation of nasal NIV by 12 to 48 hours after hospital admission (a period longer than most other included studies) and administered it in two fixed sessions (three hours per day). Most other clinical trials in this field, however, adopted flexible prescription practices, allowing quicker initiation and longer duration of treatment in accordance with participant responses (e.g. change in clinical condition). This latter approach is more likely to reflect current clinical practice in many countries where NIV is common. Removal of this study from analyses did not meaningfully impact results, most likely because of the relatively low weighting attributed to this (or any) study, in the light of the large quantity of pooled data for most review outcomes. This small study (N = 24) was also characterised by a mild baseline level of acidosis (mean admission pH of 7.33) at which significant mortality may not be expected to occur.

NIV significantly reduced length of hospital stay by more than three days. It should be noted that the (weighted) mean length of hospital stay for the usual care group was very high (17.5 days). This duration of admission is far in excess of that commonly observed in clinical practice in many countries (Chandra 2012). It remains to be seen whether the magnitude of benefit would be the same for patients admitted to clinical settings in which shorter admissions are more common. This could be an important area of future research. Only one study (Thys 2002) contributed data to the outcome of ICU length of stay, limiting wider applicability of this non‐significant finding that tended to favour use of NIV.

The high incidence of intolerance in the NIV group was not surprising, given that this finding is clearly related to the potential discomfort of NIV in the NIV group and the absence of such discomfort in the usual care group. Although this finding indicates that NIV is not well tolerated by all patients with AHRF due to AECOPD, care should be taken not to interpret this finding as indicative of harm or a reason to deny a patient the opportunity to receive NIV when indicated. When review authors explored the incidence of complications, it became clear that most complications were related to delivery of NIV (e.g. mask‐related facial pressure areas, bloating) but were of a generally mild nature with little long‐term clinical consequence (Analysis 1.7). The two studies that reported data unrelated to NIV use described significant benefits favouring NIV use; however, additional confirmatory data appear necessary to verify this finding.

Four studies provided data regarding patient‐reported ratings of perceived breathlessness. Investigators used three different measurement instruments (Visual Analogue Scale (VAS), Borg score, and verbal rating score) at various times after admission. Therefore, pooling of these data was difficult. Although we noted statistical significance for the single study (N = 60) using VAS, we believe this does not represent any preferable sensitivity to detect changes associated with NIV use. It makes clinical sense to expect that resolution of AHRF would be associated with reduced perception of dyspnoea. Hence, although data for this outcome appear limited in the extent to which they may apply beyond this review, we believe that additional research is not strongly indicated to vigorously pursue data collection for this outcome.

Acidosis has been shown to be an important prognostic factor of survival from respiratory failure in COPD; thus early correction of acidosis is an essential goal of therapy (Jeffrey 1992). This review has shown that NIV (compared with usual care) achieves more rapid correction of acidosis within the first hour. The collective observed benefits of NIV for pH, PaO₂, PaCO₂ (not statistically significant), and symptoms of dyspnoea suggest a picture of overall clinical improvement in respiratory failure status. Although data presently available are not confirmatory, it is intuitive to hypothesise that this clinical improvement may be a logical mechanism underpinning observed beneficial effects of NIV on need for endotracheal intubation and mortality. A previous study using NIV in respiratory failure secondary to exacerbations of COPD (Brochard 1990), which was not included in this review (not an RCT), reported reductions in respiratory rate and transdiaphragmatic activity with increases in tidal volume and minute ventilation. These findings support the mechanism that NIV not only rapidly improves gas exchange but also allows respiratory muscles to rest, thereby reducing respiratory muscle work in respiratory failure. NIV appears to optimise the window of opportunity for respiratory muscle recovery and for other conventional treatments (bronchodilators, oxygen, corticosteroids, antibiotics, etc.) to take maximal effect. It is interesting to note that in the current review, the outcome for PaCO₂ did not reach statistical significance; however, our post hoc exploration of this finding showed that it was heavily influenced by data derived from Dikensoy 2002 and Matuska 2006, both of which were rated as having high risk of bias owing to imbalance of outcomes at baseline. In each instance, participants in the NIV group happened to have statistically significantly worse baseline PaCO₂ levels before commencing the intervention (despite randomisation). Endpoint data recorded at one hour were used for meta‐analysis, yet these values appeared numerically worse in the NIV group than in the usual care group. Inspection of the degree of change in both studies showed NIV to be superior to usual care in both instances (NIV group improved and usual care group deteriorated in both studies). This finding may need to be interpreted with due diligence.

A specific point to consider regarding observed changes in blood acidity levels relates to the unit of measurement for the pH outcome. It is perhaps ideal to express changes in this outcome in units of hydrogen ion concentrations (H⁺) rather than pH; however the latter clearly is used more widely and is easier to interpret in the clinical domain than the former. pH is the negative log of the hydrogen ion concentration; because of the logarithmic nature of pH, one cannot assume that differences in hydrogen ion concentrations between (for example) a pH of 7.26 versus 7.27 compared with 7.27 versus 7.28 are linear. Descriptions of mean changes in acidity of 0.01 of a pH unit can therefore risk becoming meaningless. As reporting of pH in clinical trials and clinical practice regarding NIV use is far more common than reporting of use of H⁺, we opted to report data in this more conventional manner and do not advocate change. Rather, we encourage appropriate due diligence in implementation of findings related to this outcome, especially when stratification according to acidosis severity may be pertinent.