Use of noninvasive ventilation in immunocompromised patients with acute respiratory failure: a systematic review and meta-analysis

Our meta-analysis illustrated that early use of NIV could effectively reduce short-term mortality in immunocompromised patients with ARF when compared with oxygen therapy alone. In addition, the NIV strategy was associated with a reduction in the rate of endotracheal intubation and length of ICU stay.

Although our results are encouraging, several important issues merit detailed discussion. First, significant heterogeneity was observed between pooled studies in the primary outcome. This is not surprising, given the differences in the diagnostic criteria for ARF, treatment algorithms, and underlying diseases. Our sensitivity analyses showed that the trial by Squadrone and colleagues [12] probably contributed to the observed heterogeneity. Unlike other included trials, Squadrone and colleagues enrolled immunocompromised patients without a diagnosis of pneumonia, infection, or sepsis. Of note, these patients had a higher PaO₂/FiO₂ ratio, and were managed by CPAP rather than by NIPSV. After excluding this trial, the pooled result of the remaining studies still showed a reduction in mortality. Furthermore, we also demonstrated a significant reduction in the intubation rate and length of ICU stay in the NIV group, which added robustness to our primary outcome.

Second, our findings contradicted the results of the two latest RCTs [13, 14]. These two trials, although included in our meta-analysis, did not report a significant difference in clinical outcome (e.g. short-term or long-term mortality and intubation rate) among inpatients assigned to early NIV compared with oxygen therapy alone. Wermkeet al. [13] enrolled patients with mild hypoxemia, as suggested by a mean PO₂/FiO₂ ratio of 250 to 300. Moreover, 36.4% (16/44) of patients in the control group received NIV as a rescue therapy. The high crossover rate might have masked the beneficial effect, if any, of NIV in immunocompromised patients with ARF. This trial might also contribute to the negative findings in the subgroup of mild hypoxemia. In comparison, in the study of Lemiale and colleagues [14], a high-flow nasal cannula (HFNC) was used in both groups at the discretion of treating physicians.

Interestingly, HFNC was used more often in the oxygen group than in the NIV group (44% vs. 31%, p?=?0.01). HFNC is a new technique that may deliver up to 100% humidified oxygen at a high flow rate. The advantages of HFNC include a high fraction of inspired oxygen to improve oxygenation, generation of flow-dependent PEEP (2–5 cmH₂O) to improve alveolar recruitment, enhanced washout of nasopharyngeal dead space, and greater comfort in patients requiring oxygen therapy [17]. Several studies have shown that compared with conventional oxygen therapy, HFNC in immunocompetent patients with ARF could improve respiratory parameters, comfort and patient tolerance [18–20]. Moreover, in an observational cohort study of immunocompromised ICU patients with ARF, Coudroy and colleagues reported that use of HFNC was associated with a significant reduction in intubation rate and 28-day mortality compared to NIV (35% vs. 55%, p?=?0.04, and 20% vs. 40%, p?=?0.02, respectively) [21]. As a result, the use of HFNC could have greatly reduced the demand for IMV in control group, thereby diluting the benefits of NIV in these patients. More than this, it may also explain why there was no reduction in long-term mortality in the pooled analysis of patients in these two trials only. It is also noteworthy that in the study by Lemiale and colleagues [14], the overall mortality rate was much lower than in the other included RCTs (hospital mortality 32.6% vs. 45–65%). Thus, this study might provide a clue to the potential benefits of HFNC, or HFNC in combination with NIV, over NIV alone. Nevertheless, such a hypothesis should await validation by a large scale, well-designed RCT in the future.

Third, extremely high mortality rates were reported in immunocompromised patients who did not respond to conventional oxygen therapy or to NIV (Table 3); these rates were even higher than the mortality rate of 70–80% that is widely reported in previous studies [22, 23]. Despite the fact that the exact reasons remain to be clarified, such high mortality might support the recommendation against the use of IMV in this vulnerable patient population, thus favoring NIV as the first-line choice of therapy [1].

Finally, we also found that early use of NIV was associated with a significant reduction in the length of ICU stay. This encouraging result has added robustness to the conclusion that early NIV strategy is effective in immunocompromised patients with ARF. Although in clinical practice, ICU discharge is not always determined by the patient condition and needs to be individualized [24]; the less likely that a patient requires tracheal intubation, the more likely that physicians feel comfortable about the patient being discharged from ICU.

The current meta-analysis has provided evidence to support and expand the weak suggestion in the 2011 Canadian guidelines [1], i.e. use of noninvasive positive-pressure ventilation (NPPV) in immunocompromised patients with ARF. However, this study has some limitations. First, only five RCTs were included in the current meta-analysis, while four of them had a sample size of 40 to 86 patients, which more likely resulted in overestimation of the treatment effect than in studies with larger sample sizes. Second, significant heterogeneity was observed in some of our outcomes. There were remarkable differences among the included trials in the adopted definition of ARF, timing and duration of oxygen therapy or NIV, and indications for endotracheal intubation, which might lead to the observed heterogeneity, and further impair the robustness of our findings. Third, the uneven distribution of different underlying diseases among the included studies might also exert a prognostic value [4, 25, 26]. Although predefined subgroup analyses had been performed, the results should be interpreted with caution due to the small number of patients in some disease categories, i.e. patients receiving immunocompromised drugs or patients with acquired immunodeficiency syndrome.