Strong Recommendation

Chronic Obstructive Pulmonary Disease (COPD)

The best established application of NIV is to treat acute exacerbations of COPD. A dozenyears ago,Brochardetal. [4] showedthatpressure support ventilation(PSV), administered via a face mask, significantly reduced the need for intubation, duration of mechanical ventilation and ICU length of stay compared to historically-matched controls. Subsequently, six randomized controlled trials have confirmed these findings [5-11].Bott etal. [5] observed significantly greater improvements in PaCO2 as well as dyspnea scores within the first hour in a group of NIV-treated patients compared to controls. Also, there was a 10% mortality rate in the NIV group compared to 30% in controls, but this was not statistically significant unless four patients who were randomized to NIV, but did not actually receive it, were excluded from the analysis. Kramer et al. [6] subsequently found that NIV reduced the rate of endotracheal intubation to 9% from 67% in controls in a subgroup of COPD patients. This study also showed more rapid improvements in respiratory rates and blood gases in the NIV group but no significant differences in hospital lengths of stay or mortality rates, perhaps because of the small sample size. In their multicenter randomized trial, Brochard et al. [7] found not only that vital signs, blood gas values, and encephalopathy scores improved more rapidly in the NIV-treated group than in controls, but also that intubation rates (from 74-26%), complication rates (notably pneumonia and other complications from endotracheal intubation), hospital lengths of stay (from 35 to 17 days) and mortality rates (from 31 to 9%) fell significantly. A subsequent smaller trial by Celikel et al. [9] also found that NIV significantly reduced intubation rates and hospital lengths of stay (from 14.6 to 11.7 days, p<0.05) compared to controls. Plant etal. [10] randomized 236 patients with acute exacerbations of COPD to receive NIV or standard therapy administered by nurses in general medical respiratory wards. The intubation and mortality rates were significantly lower in the NIV group compared to controls (15 vs. 27%, p=0.02 and 10 vs. 20%, p=0.05, respectively). The authors confirmed earlier findings of more rapid improvements in arterial pH, respiratory rate and breathlessness in the NIV compared to the control group. Of note, the mortality benefit was not apparent in patients with pH < 7.30, and the authors surmised that this more severely ill subgroup would have faredbetter in a more closely monitored setting such as an ICU.

The only negative study [12] found that NIV failed to lower intubation or mortality rates or hospital lengths of stay, but it is notable that no intubations or mortalities occurred in the control group. Furthermore, the hospital length of stay was only one third that of the control group in the Brochard study [7]. Thus, the enrolled patients were less severely ill than those included in other randomized trials and were less likely to benefit from NIV. The most important finding of this study is that patients with relatively mild COPD exacerbations are not likely to benefit from NIV.

Taken together, the above studies demonstrate that NIV is effective in acute COPD exacerbations, not only bringing about rapid symptomatic and physiologic improvements, but also significantly reducing the need for intubation, complica tion and mortality rates, and, in some studies, hospital lengths of stay. A metaanalysis [13] combining the results of some of these studies came to a similar conclusion about the need forintubation and mortalityrate. Based onthis evidence, consensus groups have opined that NIV is indicated as the ventilator mode of first choice in selected patients with COPD exacerbations [14].

Cardiogenic Pulmonary Edema

Along with COPD exacerbation, cardiogenic pulmonary edema is one of the two most common indications for non-invasive positive pressure techniques in the acute setting [15]. The evidence supporting the use ofpositive pressure in pulmonary edema, however, is stronger for the use of continuous positive airway pressure (CPAP) than for NIV (in which air pressure is increased during inspiration). CPAP has been used for many decades to treat cardiogenic pulmonary edema and the rationale for its application is quite strong. CPAP rapidly improves oxygenation by re-expanding flooded alveoli. It also increases functional residual capacity (FRC), thus more favorably positioning the lung on its compliance curve [16], reducing the work of breathing. Further, it can improve cardiac performance by raising pericardial pressure [16-18], lowering transmural pressure and thereby decreasing afterload [19, 20]. This favorable hemodynamic effect is most likely to occur when fillingpressures are high and ventricular performance is poor. However, inpatients with relatively low filling pressures and good ventricular performance, the hemodynamic effects of CPAP can be adverse, by diminishing venous return [17].

Several randomized studies have demonstrated that CPAP is effective in treating acute pulmonary edema [21-25]. Rasanen et al. [21] randomized 40 patients with cardiogenic pulmonary edema to either face mask CPAP (10 cmH2O) or standard medical therapy and demonstrated a rapid improvement in oxygenation and respiratory rate. Lin and Chiang [23] randomized 55 patients to face mask CPAP adjusted along with the inspired oxygen fraction (FiO2) to maintain PaO2 = 80 mmHg. CPAP significantly lowered the rate of intubation (17.5 vs. 42.5%, p<0.05), but no significant difference in mortality rate was observed. Bersten et al. [24] and Lin et al. [25] subsequently performed similar randomized studies on 39 and 100 patients, respectively, demonstrating the same favorable effects on oxygenation, respiratory rates and the need for intubation. The Bersten et al. study [24] also showed a significant reduction in ICU stay among CPAP-treated patients and the Lin et al. study [25] showed trends for improved hospital mortality rates.

Fewer controlled trials have been performed to determine whether NIV (usually pressure support plus positive end-expiratory pressure [PEEP]) is effective for acute pulmonary edema. Hypothetically, this approach might be more effective than CPAP alone, because a greater reduction in the work of breathing and more rapid alleviation of hypercapnia and dyspnea might be superimposed on the benefits achieved with CPAP.

Several uncontrolled trials have demonstrated low intubation and complication rates [26-30], supporting the contention that NIV is an effective therapy for acute pulmonary edema. However, one of these studies noted a high mortality rate in patients with acute myocardial infarction and cautioned about the use of NIV in such patients [30,31]. In a randomized, prospective trial of40 patients treated with mean inspiratory and expiratory pressures of 15 and 5 cmH2O, respectively, Masip etal. [32] found a significantlylower rate of intubation inNIV-treated patients (5%) compared to oxygen-treated controls (33%) (p=0.037). While oxygenation improved more rapidlyin the NIV treated group compared to control, hospital lengths of stay and mortality rates were similar in the two groups. Sharon and colleagues [33] also performed a randomized trial that compared NIV plus low dose nitroglyc-erin versus high dose nitroglycerin in 40 patient with acute pulmonary edema. Patients treated with NIV hadhigher intubation (80 vs. 20%), myocardial infarction (55 vs. 10%) and death (10% vs. none) rates compared to controls (all p<0.05), leading the authors to conclude that NIV was less effective and potentially harmful compared to high dose nitroglycerin. However, this inference is unjustifiedbecause the groups were not comparable and the inordinately high intubation rate in the NIV group (80%) is difficult to explain.

Superiority of NIV over standard therapy for acute pulmonary edema is not surprising, but the question of most interest is whether NIV is superior to CPAP alone. If not, then the simpler and less expensive CPAP devices could be used to treat acute pulmonary edema. Only one randomized trial has thus far compared CPAP to NIV to treat acute pulmonary edema [34]. Although this trial showed significantly more rapid reductions in respiratory rate, dyspnea scores and hyper-capnia in the NIV compared to the CPAP-treated group, the study was stopped prematurely after enrollment of 27 patients because of a greater myocardial infarction rate in the NIV group. This difference may have been attributable to unequal randomization because more patients in the NIV group presented with chest pain, but the results nonetheless raise concerns about the safety of ventilatory techniques used to treat acute pulmonary edema complicated by cardiac ischemia or infarction.

A more recent randomized controlled trial compared NIV to high flow oxygen by mask and demonstrated no statistically significant difference in the myocardial infarction rate between the two groups [35]. However, this study had limitations including a small number of patients and possibly inadequate pressures, considering that respiratory rate was not lowered more significantly by NIV. Presently, evidence on whether NIV is superior to CPAP is inconclusive; NIV lowers PaCO2 and dyspnea scores more rapidly, but it is unclear whether outcomes like intubation or mortality rate, or hospital length of stay differ between the modalities. Pending further studies, the most sensible current recommendation is to use CPAP (10 cmH2O) initially and consider switching to NIV if the patient is found to have substantial hypercapnia or unrelenting dyspnea. This is in line with the conclusion of a meta-analysis that found insufficient evidence to support the use of NIV in preference to CPAP to treat acute pulmonary edema [36].

Immunocompromised Patients

Evidence is accumulating to support the use of NIV in immunocompromised patients with acute respiratoryfailure. Antonelli et al. randomized 40 patients who developed acute respiratory failure following solid organ transplant to NIV vs.

conventional therapy. Patients treated with non-invasive positive pressure ventilation more often had increases in PaO2/FiO2 ratios (60 vs. 25%, p=0.03) and lower intubation (20 vs. 70%, p=0.05) and mortality rates (20 vs. 50%, p=0.05) [37]. In addition, the incidence of severe sepsis and shock was significantly reduced in the NIV group. More recently, another randomized trial of 52 patients with various immunocompromised states, mainly related to hematological malignancy, demonstrated reductions in the need for intubation (46 vs. 76%, p=0.03) and serious complication and mortality rates (both 50 vs. 80%, p=0.02) in NIV-treated patients compared with conventionally-treated controls [38]. The mortality of patients with hematological malignancies requiring intubation has been reported to exceed 80% in some series [39-45], largely because of septic and hemorrhagic complications. Thus, the avoidance of intubation in this patient population is a desirable outcome and the use of NIV is, therefore, justifiable in selected patients with immunocompromised states. It is important to note, however, that the authors of these studies stress the importance of early initiation, before progression to severe compromise [38].

Recommended with Reservations


The success of NIV in treating COPD raises the possibility that it would also be beneficial in acute asthma. However, the lack of randomized controlled trials to confirm this hypothesis weakens the indication. Furthermore, the pathophysiologies and natural histories of COPD and asthma differ markedly and, thus, it is not fair to assume that one would respond to NIV in the same way as the other. However, cohort studies have reported successful outcomes with NIV in severe status asthmaticus complicated by CO2 retention [27, 46]. In one study, only two of 17 asthmatics required intubation after starting NIV, with PaCO2 falling from an average of 65 to 52 mmHg and respiratory rate from 29 to 20/min (p=0.002 and 0.0001, respectively), after 2 hours of therapy [46]. In a retrospective analysis of 33 asthmatic patients who were deemed to be candidates for NIV, the outcomes of 11 patients managed with invasive mechanical ventilation were compared with 22 managed non-invasively [47]. Gas exchange and vital signs improved rapidly in the NIV group and only 3 patients eventually required endotracheal intubation. A recent randomized, controlled trial on the use of NIV in acute asthma found no significant advantages attributable to the use of NIV [48]. However, the study was severely under-powered and the authors reported that bias on the part of emergency room physicians favoring NIV interfered with enrollment because of the concern that enrolled patients might become controls and not receive NIV therapy [48].

Despite the lack of convincing evidence to support the use of NIV in acute severe asthma, a trial of NIV in carefully selected and monitored patients is justifiable based on the anecdotal evidence. While no selection guidelines have been established, a reasonable approach would be to use NIV in patients who fail to respond promptly to standard initial medical therapy (i.e., within the first hour), but who have not developed contraindications to NIV (see patient selection section). Caution is advised because asthmatics may deteriorate abruptly and delay of needed intubation is a risk. Some studies indicate that aerosolized medication maybe more effectively delivered via the NIV circuit compared to a standard nebulizer [49] and, anecdotally, NIV has been combined with heliox to treat status asthmaticus (personal observation), although no data are available to support this practice.

Cystic Fibrosis

Like asthmatics, patients with cystic fibrosis have airway obstruction and might be expected to respond to NIV like COPD patients. However, only a few anecdotal reports support the use of NIV in acute exacerbations of cystic fibrosis [50, 51]. Hodson et al. [50] used NIV to treat six cystic fibrosis patients with baseline forced expiratory volume in one second (FEVi) ranging from 350 to 800 ml who developed acute superimposed on chronic CO2 retention. These patients, with initial PaCO2 ranging from 63 to 112 mm Hg, were supported for periods ranging from 3 to 36 days. Four patients survived until heart-lung transplantation could be performed. These same investigators recently reported their experience using NIV in 113 cystic fibrosis patients suffering acute deteriorations [51]. Of the 90 patients (median FEV1/FVC ratio 0.51) who were either on, orbeing evaluated for, the lung transplant waiting list, 28 patients had successfully received lung transplantation and 10 others were still on the list. The authors noted that NIV improved hypoxia but not hypercapnia. These case series suggest that NIV is helpful as a rescue therapy in supporting acutely deteriorating cystic fibrosis patients providing a 'bridge to transplantation'. Despite the lack of evidence from randomized, controlled trials, using NIV to avoid intubation in appropriately selected patients with acute exacerbations or with deteriorating disease who have increasing CO2 retention is sensible, particularly in view of the practice at some lung transplantation centers to remove intubated patients from the transplant list.


The application of NIV to treat acute pneumonia has generated conflicting reports. Early on, pneumonia was associated with a poor outcome in patients treated with NIV [52]. A more recent study demonstrated that outcomes are significantly worse for patients with acute pneumonia compared to those with acute pulmonary edema who have a similar degree of hypoxemia (intubation rate 38 vs. 6.6%, p<0.05). In some of the early studies, part of the difficulty in assessing the efficacy of NIV in patients with 'pneumonia' was a failure to offer clear diagnostic criteria.

One randomized trial has been performed on patients with 'severe community-acquired pneumonia', defined as patients with severe hypoxemia (PaO2/FiO2 < 200 mmHg) and respiratory distress (respiratory rate > 35/min). In this study, NIV reduced the need for intubation (21 vs. 50%, p=0.03), shortened ICU length of stay (1.8 vs. 6 days, p=0.04), and reduced mortality rate among the COPD subgroup of patients two months after hospital discharge [53]. However, further analysis showed that the COPD subgroup was the only one to benefit from NIV. More recently, a prospective trial focusing on NIV use in non-COPD patients with severe community-acquired pneumonia observed that 22 of 24 patients had initial improvements in oxygenation and respiratory rates after starting NIV, but 66% eventually required intubation [54].

Although the authors of these trials concluded that NIV should be used routinely in patients with community-acquired pneumonia, the lack of controls in the latter study, and the failure to demonstrate benefit in the non-COPD subgroup in the controlled trial, undermine this recommendation. Presently, NIV is indicated in appropriate COPD patients with community-acquired pneumonia, but the benefit of NIV in pneumonia patients without COPD has not been established and, as such, NIV should be used with caution in such patients.

Facilitation of Extubation and Weaning

NIV has been used to facilitate early extubation after bouts of acute respiratory failure and to avoid extubation failure when patients deteriorate following extubation. In the first instance, NIV is used as a 'crutch' to permit early extubation in patients who fail to meet standard extubation criteria. The rationale is that outcomes can be improved by avoiding the complications of prolonged intubation such as nosocomial infection and upper airway trauma. The first controlled trial to test this idea enrolled 50 COPD patients who had been intubated for 48 hours and failed a T-piece trial [55]. They were randomized to prompt extubation and NIV or continued intubation with standard weaning. The NIV group had higher overall weaning rates after 60 days (88 vs. 68%), shorter durations of mechanical ventilation (10.2 vs. 16.6 days), briefer stays in the ICU (15.1 vs. 24 days) and improved 60 day survival rates (92 vs. 72%) compared to controls, respectively (all p<0.05). In addition, NIV-treated patients had no nosocomial pneumonias compared to seven in the control group.

A second trial of 33 patients randomized to early extubation and NIV or conventional intubationwith standardweaningaddressedthe question ofwhetherNIV should be used as a 'systematic' extubation technique [56]. NIV-treated patients had shorter durations of invasive mechanical ventilation than the control group (4.56 vs. 7.69 days, p<0.05), but the total duration of mechanical ventilation (including NIV) was actually greater in the NIV group (16.1 vs. 7.69 days, p= 0.0001). Furthermore, patients in the NIV group had similar eventual weaning and mortality rates, and although they had a tendency toward fewer complications (9 vs. 16%), the difference was not statistically significant. The authors concluded that NIV shortens the duration of invasive mechanical ventilation, but they were unable to demonstrate significant improvements in other outcomes. A third controlled, preliminary trial of 25 patients with various etiologies for their acute respiratory failure also found a significantly shorter duration of invasive mechanical ventilation, but extubation failure rate was higher (41% vs. none in controls, p<0.05) among patients extubated early to NIV [57].

Although the randomized controlledtrials support the ideathat earlyextubation to NIV can improve some outcomes of some mechanically ventilated patients, the results are mixed, raising questions about whether NIV should be used routinely to shorten the duration of invasive mechanical ventilation. Clinicians are advised to exert caution when selecting patients for early extubation, reserving the technique mainly for patients with acute on chronic respiratory failure (i.e., COPD patients) who are unable to meet standard extubation criteria but are otherwise good candidates for NIV. Those with prior difficult intubations, multiple co-morbidities, copious secretions, weakened cough, or the need for high levels of pressure support (>20 cmH2O) should not be considered for early extubation.

NIV can also potentially be used to avoid re-intubation in patients who fail extubation. Extubation failure occurs after 5-20% of planned [58] and 40-50% of unplanned extubations [59] and has been associated with a mortality of 43% compared to only 12% in those who succeed after extubation [58].Several nonrandomized studies support the idea that NIV can be used to avert the need for re-intubation in patients with extubation failure, thereby avoiding the complications and mortality of prolonged intubation [27,60-62].0ne of these studies found that 30 COPD patients with post-extubation hypercapnic respiratory insufficiency treated with NIV required re-intubation less often (20 vs. 67%, p<0.05) and had shorter ICU lengths of stay than 30 historically matched controls [62]. In a subsequent randomized trial of patients at high risk for extubation failure and who developed respiratory distress within 48 hours of extubation, however, NIV did not reduce the need for intubation, duration of mechanical ventilation, length of hospital stay or mortality [63].

To date, only one randomized trial has examined NIV as a 'prophylactic' technique; i.e., using it in all extubated patients to see if it lowers the extubation failure rate [64]. Ninety-three consecutive patients were enrolled, 56 after planned and 37 after unplanned extubations. Thirteen (28%) of the 47 patients randomized to NIV required re-intubation compared to only 7 (15%) of the 46 controls who received oxygen supplementation alone (p > 0.05). Although there was a problem with randomization in that more patients with unplanned extubations were assigned to the NIV group and these constituted most of the failures, the authors concluded that their results did not support the "indiscriminate" use of NIV to avoid post-extubation failure. Although NIV should certainly not be used routinely in post-extubation patients, just which patients with extubation failure should receive NIV to avoid re-intubation is unclear, considering the conflicting trial results. The most reasonable approach currently is to evaluate each patent individually, applying the selection criteria discussed below. The criteria are applicable to those patients who have underlying pulmonary edema or COPD as the cause of their respiratory distress, and should be applied with caution in other patients. Further studies must be done to determine which subcategories of patients might respond favorably to NIV.

Postoperative Patients

Some early case series reported the use of NIV to treat respiratory insufficiency after surgery in patients with PaCO2 > 50 mmHg, PaO2 < 60 mmHg, or evidence of respiratory muscle fatigue [65-68]. Using nasal bilevel positive airway pressure

(BiPAPĀ®), these studies reported prompt reductions in respiratory rate and dyspnea scores, improvements in gas exchange, and high success rates in avoiding the need for reintubation. Subsequently, prophylactic postoperative use of NPPV in lung resection [69] and post-gastroplasty patients [70] has been shown to improve gas exchange and pulmonary function, respectively, compared to controls treated with oxygen alone. More recently, a randomized trial of NIV in post lung resection patients with acute respiratory insufficiency showed significant reductions in the need for intubation, ICU length of stay and mortality rate compared to conventionally-treated controls [71]. Thus, accumulating evidence now supports the use of NIV in selected postoperative patients to maintain improved gas exchange and avoid re-intubation and its attendant complications. NIV should not be used in patients with recent neck, upper airway or esophageal surgery, and caution should be exercised after recent upper gastrointestinal surgery that penetrates the mucosal barrier.

Do-Not-Intubate (DNI) Patients

The use of NIV to treat respiratory failure in patients who have declined intubation is common in some centers, accounting for some 10% of acute applications in a recent survey [72]. Some have argued that there is little to lose with this approach, as it may reverse the acute deterioration or, at least, provide relief of dyspnea and a few extra hours to finalize affairs [73]. However, others have argued that this merely prolongs the dying process, consumes resources inappropriately, and may add to discomfort or counter patients' wishes about avoidance of life-prolonging measures [74]. In one study of 30 patients, mostly with COPD, in whom endotra-chealintubationwas "contraindicated or postponed," eighteen (60%) patientswere successfully supported withNIV andweaned [75]. Anotheruncontrolled series [76] observed a similar response to NIV among 26 patients with acute hypercapnic and hypoxemic respiratory failurewho refused intubation. Inamore recent prospective survey of 113 DNI patients treated with NIV, survival to hospital discharge was 72% and 52% for acute pulmonary edema and COPD patients, respectively, whereas it was less than 25% for those with diagnoses of pneumonia or cancer [72]. Thus, NIV is indicated in DNI patients with acutely reversible processes that are known to respond well, such as acute pulmonary edema or COPD exacerbation. However, if NIV is to be used for DNI patients, patients and/or their families should be informed that NIV is being used as a form of life support that maybe uncomfortable and can be removed at any time.

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