Is a patient’s failure to respond to NPPV a marker of disease severity, or a sign that earlier intubation is warranted?

Noninvasive positive-pressure ventilation (NPPV) involves the delivery of mechanically assisted breaths without the use of an endotracheal or tracheostomy tube. Currently, ventilation is delivered via either a nasal mask or a full-face mask. Several early applications of NPPV in acute respiratory failure used volume-cycled ventilators. Most controlled trials, however, have been performed using pressure-limited ventilation. This has consisted of either pressure-support ventilation (PSV) or bilevel positive airway pressure ventilation. Bilevel positive airway pressure ventilation delivers both inspiratory PSV and an expiratory pressure that is similar to positive end-expiratory pressure (PEEP) or continuous positive airway pressure (CPAP). Bilevel positive airway pressure can be delivered using most conventional ventilators found in intensive care units (ICUs) and by some home units used primarily to treat sleep apnea. The two types of systems differ in several ways and should not be confused with each other.

NPPV has been applied in a wide variety of acute care settings.1 Patient selection has been critical to the reported success of NPPV. Reports documenting the successful application of NPPV have involved mostly case series that were without control subjects or that had only historical control cases. Exceptions, however, have been made for acute exacerbations of chronic obstructive pulmonary disease (COPD) and acute cardiogenic pulmonary edema; for both, studies2-8 involving prospective, randomized, controlled trials have confirmed the benefits of this approach.


The application of CPAP by mask for patients with acute cardiogenic pulmonary edema has been successful in decreasing the need for endotracheal intubation (0 percent to 24 percent versus 35 percent to 50 percent for controls) when used as an adjunct to conventional therapy.2,3 No differences in mortality or length of hospital stay have been found. The application of positive airway pressure increases intrathoracic pressure, decreasing preloading by decreasing venous return and decreasing afterloading by decreasing transmural aortic pressure. Oxygenation improves through a reduction in intrapulmonary shunting.

CPAP is the preferred modality of NPPV for patients with acute cardiogenic pulmonary edema. A randomized trial4 compared the application of bilevel positive airway pressure (inspiratory pressure [IPAP]: 15 cm H2O; expiratory pressure [EPAP]:

5 cm H2O) to a CPAP level of 10 cm H2O in patients with acute cardiogenic pulmonary edema. No differences were seen in intubation rate, mortality, or length of stay. The trial was prematurely terminated when it was discovered that the bilevel positive airway pressure patients had incurred an increased frequency of acute nontransmural myocardial infarction (10 of 14 patients) compared with the CPAP group (4 of 13 patients). Because more of the bilevel patients had chest pain and/or a left bundle-branch block at the time of randomizing the samples, however, this finding may simply represent an artifact of randomization among a relatively small number of patients.


Four prospective, randomized controlled trials5-8 of NPPV provide strong evidence for the efficacy of NPPV in selected patients with acute or chronic hypercapnic COPD exacerbations.9-10 A recent meta-analysis11 revealed a significantly decreased need for intubation (odds ratio [OR]=0.29; 95 percent confidence interval [CI], 0.15 to 0.59) and significantly decreased mortality (OR=0.20; 95 percent CI, 0.11 to 0.36 percent) in the NPPV patients. Expressed differently, the number of treatment episodes needed to prevent one COPD death by using NPPV instead of conventional therapy ranges from 5 to 15 patients. The number needed to prevent one intubation using NPPV is only two to three patients.

These results remain controversial.9,12 In all of these studies, patients who required immediate intubation were excluded. In one study,7 only 31 percent of COPD patients were ultimately randomized. Thus, the use of NPPV has been proven to be effective, but only for a subset of COPD patients with acute hypercapnic exacerbations. Unfortunately, the prospective identification of patients who will succeed with NPPV is difficult.1,13,14 In one study,15 patients who were more acutely ill (mean severity of disease as classified using the Acute Physiology and Chronic Health Evaluation (APACHE) II system=21ñ4) were more likely to fail with NPPV than patients who were not as sick (mean APACHE II=15ñ4). In another trial,16 only the magnitude of hypercapnic acidosis was associated with subsequent success or failure (pH 7.28ñ0.04 versus 7.22 ñ0.08, respectively). In both trials, the presence of pneumonia also made a successful outcome less likely.


Studies of patients with COPD exacerbations have shown the efficacy of several modes of NPPV, including assist-control ventilation,6 PSV,7 bilevel positive airway pressure,8 and a particular bilevel positive airway pressure delivery system first commonly used in the home.5 NPPV, like conventional ventilation, has a salutary effect by decreasing the work of breathing. Transdiaphragmatic pressure, the diaphragmatic pressure-time product, and diaphragmatic electromyographic amplitude are all decreased through the application of mask PSV to patients with exacerbations of COPD.17 Assist-control volume-cycled ventilation delivered by mask reduces work of breathing more than PSV,18 but is no more effective than mask PSV at preventing the intubation of COPD patients.19 PSV is better tolerated by patients than assist-control mask ventilation, since the patient’s own breath is sensed and assisted by the ventilator.19

When expiratory pressure is added to mask PSV, gas exchange is further improved in COPD patients, and the diaphragmatic pressure-time product decreases to values lower than those seen for PSV alone.20 This effect is probably due to a partial overcoming of the autoPEEP present in these individuals. Gas exchange improves during bilevel positive airway pressure ventilation because of an increase in alveolar ventilation (rather than improved ventilation-perfusion matching).21 As a result, bilevel positive airway pressure has become the preferred mode of NPPV administration for COPD patients.22


The portable bilevel positive airway pressure delivery system first commonly used in the home was used in one of the four COPD randomized controlled trials5 with good results. Portable ventilators of this type have been criticized23 due to their inability to deliver precise and/or high oxygen concentrations consistently; the potential for carbon dioxide rebreathing during their use, although this may be obviated at added expiratory pressures of more than 4 to 8 cm H2O24; and their lack of monitors with alarms. Microprocessor-controlled ventilators typically found in ICUs provide NPPV with bilevel positive airway pressure at a precise fraction of inspired oxygen (Fio2); have separate inspiratory and expiratory tubing, thereby avoiding the promotion of rebreathing; and have the ability to monitor for high airway pressure, large mask leaks, or patient disconnection. ICU ventilators may be preferable to portable models when NPPV is being used for acute respiratory failure.


Of four controlled trials using NPPV in acute exacerbations of COPD, two used nasal masks5,6 and two used facial masks.7,8 Patients with facial masks are less easily checked for aspiration than patients with nasal masks.25 A full facial mask may be preferable, however, when patients start using NPPV.13 The nasal air passages contribute significantly to airway resistance, which can undermine the benefit of a low level of PSV. In addition, most patients in acute respiratory failure are mouth breathers. The development of large mouth leaks in patients treated using nasal masks is also associated with a worse outcome.15


Patients who require immediate intubation or who have hemodynamic instability should not be considered candidates for NPPV, and they have been routinely excluded from enrollment in controlled trials. When NPPV was used as first-line therapy at a center where personnel had been specially trained, it was instituted for only 24 percent of patients with acute respiratory failure.26 Thus, NPPV should be employed in only a minority of patients who have acute respiratory failure. Selection and exclusion criteria for the use of NPPV for acute respiratory failure, as advocated by a consensus conference of the American Association for Respiratory Care,22 are shown in Table 1.


We retrospectively reviewed the medical records of patients (admitted consecutively) who received NPPV for acute respiratory failure. This research was undertaken in order to determine what factors might differentiate patients who benefit from this modality from those who do not. Eighty-four patients who received NPPV at Henry Ford Hospital, Detroit, over a 24 month period were identified. Inclusion criteria for the study were (1) acute respiratory distress or acute respiratory failure on admission (based on dyspnea, a respiratory rate of more than 24 breaths per minute or a result of less than 200 for Po2 divided by Fio2, a Paco2 of more than 45 mm Hg, or a pH of less than 7.35) and (2) the use of NPPV to avoid intubation. The decision to intubate in individual case was undertaken by an attending physician. There were no predefined criteria for intubation.

Of the 84 patients identified, 52 were enrolled in the study. For 42 of them, NPPV was used for the first time in their lives. For the other 10 enrollees, a portable bilevel positive airway pressure delivery system had already been used at home for obstructive sleep apnea (n=7), kyphoscoliosis, (n=2), or multiple sclerosis (n=1). The 32 NPPV users identified but not enrolled were not in acute respiratory distress or acute respiratory failure and were simply continuing to use the particular bilevel positive airway pressure delivery systems that they used at home.

NPPV was implemented for the study patients according to the methodology described by Abou-Shala and Meduri.1 Response to ventilation was assessed by recording Fio2 or oxygen flow in liters per minute, inspiratory airway pressure expressed as IPAP or PSV, expiratory airway pressure expressed as EPAP or CPAP, duration of ventilation, duration of ICU stay, and best arterial blood gas (ABG) levels during the first 24 hours of NPPV (with corresponding respiratory rates, heart rates, and blood pressures). The patient was considered a responder if the patient avoided intubation. A nonresponder was defined by the subsequent need for endotracheal intubation following NPPV use. Two-tailed t-tests were performed for mean differences in continuous variables. For categorical variables, a c2 test was performed. Where cell sizes were too small, a Fisher’s exact test was used.

There were 33 (63 percent) responders and 19 (37 percent) nonresponders. Responders were more than 7 years younger, on average, than nonresponders, but this difference was not significant (P=.09). In addition, there were no differences attributable to gender; race; percentage of home bilevel positive airway pressure used; presence of asthma, COPD, pneumonia, congestive heart failure, obesity-hypoventilation, or restrictive lung disease; or mean respiratory rates, heart rates, blood pressures, or ABG levels upon admission (Table 2, page 39).

Responders did have a significantly lower mortality rate (n=2, 6.1 percent) compared with nonresponders (n=7, 36.8 percent [P=.008]). They had also shorter ICU stays: 4.3 versus 14.4 days (P=.004). Analysis of demographic and physiologic variables at the initiation of NPPV did not reveal any specific factor that would reliably predict the success of this method. Clinical response to mask ventilation, however, differed significantly between responders and nonresponders in terms of mean respiratory rate, mean Po2 , mean pH, mean change in respiratory rate, mean change in Pco2, and mean change in pH (Table 3, page 40).

Our data indicate that at the time of initial presentation, no variable is capable of predicting the potential success or failure of mask ventilation. Nevertheless, several variables may predict further deterioration in the acute respiratory failure of patients using NPPV: mean respiratory rate, Po2, pH, mean change in respiratory rate, Pco2, and pH. Thus, the evaluation of changes in these parameters during the first few hours following the initiation of NPPV should lead to prompt recognition of the patients who will respond (and prevent unnecessary delay in the endotracheal intubation and conventional mechanical ventilation of nonresponders). This finding is compatible with the observations of others.26

There are significant differences in mortality and length of ICU stay between those patients who tolerate NPPV and those who do not. This may simply be a marker of disease severity: more acutely ill patients become nonresponders and are then, therefore, at greater risk of death. We were unable to discriminate between responders and nonresponders a priori. Perhaps the high mortality rate of nonresponders might have been ameliorated if there had been earlier identification of failure (with prompt intubation following that identification).

Because mortality is disproportionately clustered among nonresponders, consideration should be given to the possibility that delaying the intubation of nonresponders poses some additional risk to these patients when they are later ventilated conventionally. Only one of the randomized controlled studies done on COPD patients compared the mortality rate of nonresponders to that of patients who were conventionally treated in the control group.7 Unfortunately, this comparison was not statistically tested. At present, the question of whether NPPV failure may carry the risk of increased mortality remains unanswered.

Petr Bachan, MD, is a resident in the Internal Medicine Program, Henry Ford Hospital, Detroit. Robert C. Hyzy, MD, is an attending physician in pulmonary and critical care medicine, also at Henry Ford Hospital.


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