Abroug et al. Ann. Intensive Care (2017) 7:59 DOI 10.1186/s13613-017-0273-6 REVIEW Open Access Noninvasive ventilation with helium– oxygen mixture in hypercapnic COPD exacerbation: aggregate meta‑analysis of randomized controlled trials Fekri Abroug1*, Lamia Ouanes‑Besbes1, Zeineb Hammouda1, Saoussen Benabidallah1, Fahmi Dachraoui1, Islem Ouanes1 and Philippe Jolliet2 Abstract When used as a driving gas during NIV in hypercapnic COPD exacerbation, a helium–oxygen (He/O2) mixture reduces the work of breathing and gas trapping. The potential for He/O2 to reduce the rate of NIV failure leading to intubation and invasive mechanical ventilation has been evaluated in several RCTs. The goal of this meta-analysis is to assess the efect of NIV driven by He/O2 compared to air/O2 on patient-centered outcomes in hypercapnic COPD exacerbation. Relevant RCTs were searched using standard procedures. The main endpoint was the rate of NIV failure. The efect size was computed by a fxed-efect model, and estimated as odds ratio (OR) with 95% confdence interval (CI). Additional endpoints were ICU mortality, NIV-related side efects, and the length and costs of ICU stay. Three RCTs fulflled the selection criteria and enrolled a total of 772 patients (386 patients received He/O2 and 386 received air/O2). Pooled analysis showed no diference in the rate of NIV failure when using He/O2 mixture compared to air/O2: 17 vs 19.7%, respectively; OR 0.84, 95% CI 0.58–1.22; p 0.36; I2 for heterogeneity 0%, and no publication bias. ICU mortality = 2 = was also not diferent: OR 0.8, 95% CI 0.45–1.4; p 0.43; I 5%. However, He/O2 was associated with less NIV-related adverse events (OR 0.56, 95% CI 0.4–0.8, p 0.001),= and a shorter= length of ICU stay (diference in means 1.07 day, 95% CI 2.14 to 0.004, p 0.049). Total hospital= costs entailed by hospital stay and NIV gas were not diferent:= − dif‑ − − = ference in means 279$, 95% CI 2052–1493, p 0.76. Compared to air/O2, He/O2 does not reduce the rate of NIV failure in hypercapnic= − COPD exacerbation.− It is, however,= associated with a lower incidence of NIV-related adverse events and a shortening of ICU length of stay with no increase in hospital costs. Keywords: COPD, Exacerbation, Acute respiratory failure, Noninvasive ventilation, Helium Background clinical and technological aspects of NIV (defning opti- Noninvasive ventilation (NIV) has become a standard of mal indications, selection of ventilators and interface, care in COPD patients with acute exacerbation requir- improvements in patient–ventilator synchrony) has been ing ventilatory support [1–4]. Avoiding tracheal intuba- associated with substantial advances in NIV success tion drastically reduces the rate of ventilator-associated rates, allowing a wide range of patients to be managed pneumonia (VAP), antibiotic use, the time spent under entirely by this technique, thereby minimizing the risk of mechanical ventilation, ICU length of stay, and associ- complications inherent to conventional invasive ventila- ated mortality [5–9]. Te sustained mastering of the tion [2, 8, 9]. Despite these advances, it is believed that an additional success margin is possible, leading to further reduction in the number of patients still in need of inva- *Correspondence: [email protected] 1 Intensive Care Unit, CHU Fatouma Bourguiba, Research Laboratory sive ventilation. One such area of potential progress is the LR12SP15, University of Monastir, 5000 Monastir, Tunisia gas used for ventilation [10–12]. Full list of author information is available at the end of the article © The Author(s) 2017. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. Abroug et al. Ann. Intensive Care (2017) 7:59 Page 2 of 11 Compared to air–oxygen (air/O2), a mixture of helium administration, minimum NIV duration with a given and oxygen (He/O2) has been consistently shown to con- gas mixture during the frst 24 h, composition of the gas vey numerous benefcial efects in the setting of increased administered between NIV sessions (whether helium/ airway resistance owing to its lower density. Indeed, the O2 or air/O2), type of associated medications, and crite- lower density of helium enhances the transition from ria for primary and secondary endpoints. Disagreements a turbulent to a laminar fow, thereby reducing density- were resolved by consensus. dependent components of airway resistance within bron- Data were extracted to allow quality assessment of the chi with increased resistance, as is the case in COPD included studies. Te risk of bias tool from the Cochrane exacerbation [10–16]. Tese efects translate into a Handbook was used [18]. reduction in dynamic hyperinfation and a lower work of breathing [10, 15, 17]. Tese studies provide sound scien- Data synthesis tifc grounds to anticipate a reduction in NIV failure rate In this meta-analysis, the primary endpoint was the rate when using He/O2 instead of air/O2 in COPD exacerba- of NIV failure during the index ICU stay. Te second- tion requiring ventilatory support [10]. Tis hypothesis ary endpoints included the intubation rate per se as the has been tested in randomized controlled trials (RCTs). defnition of NIV failure was not uniform; in one study, Te aim of the present systematic review and meta- the failure rate was a composite of necessity of intuba- analysis is to compare the efect of He/O2 and air/O2 NIV tion and/or death without intubation during the ICU on patient-centered clinical outcomes. stay [19]. Additional endpoints were ICU mortality, the length of ICU stay, and the costs of ICU stay. Safety was Methods assessed through the number of serious adverse events Search strategy and study selection related to He/O2 mixture, and the number of episodes of Relevant studies were searched in MEDLINE, EMBASE, complication related to NIV. Te latter consisted of facial and Science Citation Index with the restriction of ran- skin necrosis, gastric distension, pneumothorax, and domized clinical trial for article type published up to nosocomial pneumonia. NIV failure was not considered September 20, 2016, with the following MeSH terms: an NIV adverse efect since it was counted separately as [“non-invasive ventilation” or “Bilevel”] AND [(“pulmo- the primary outcome. nary disease, chronic obstructive”[MeSH Terms] OR (“pulmonary”[All Fields] AND “disease”[All Fields] AND Statistical analysis “chronic”[All Fields] AND “obstructive”[All Fields]) OR For binary outcomes (NIV failure rate, intubation rate, “chronic obstructive pulmonary disease”[All Fields] OR mortality, NIV complications, and adverse efects of He/ “copd”[All Fields]) AND “exacerbation”[All Fields] AND O2 mixture), we reported the efect sizes estimates as [“heliox” or “helium–oxygen” or “helium”]. We have also odds ratios (ORs) with 95% confdence intervals (CIs). conducted a manual search in journals and contacted For the length of ICU stay, and the diference in costs authors of trials. of the total hospitalization per patient, results were expressed as diference of means and 95% CIs. Only two Study selection out of three included studies reported the total costs per We included all randomized controlled clinical tri- patient, which consisted of both the costs of hospital als designed to evaluate the efcacy and safety of NIV stay and those of the gas used for noninvasive ventila- using a mixture of helium and oxygen to ventilate COPD tion. Te frst study was a Swiss one [20], and expressed patients with acute hypercapnic respiratory failure. the expenses in US$, while the second was a multicenter Standard treatment (e.g., bronchodilators and antibiot- study and reported detailed costs in French patients rely- ics) had to be comparable in control and intervention ing on diagnosis-related group (DRG) tools [19]. In the arms. Patients included in these studies were adults aged latter, costs were expressed in euros, and converted to € 18 and older with COPD diagnosed on clinical criteria US$ (1 = 1.1386US$). and respiratory function tests. Statistical signifcance was set at p < 0.05 for hypoth- esis testing and p < 0.1 for heterogeneity testing. We Data extraction and study characteristics measured heterogeneity and expressed it as I2, with Two independent evaluators (FA and LOB) selected stud- suggested thresholds for low (I2 25–49%), moderate 2 2 = ies according to the inclusion criteria and extracted the (I = 50–74%), and high (I ≥ 75%) values. We used a following: type and baseline characteristics of included fxed-efect model which assumes that studies included patients, the criteria for NIV, type and composition in the meta-analysis should share a common efect size, of He/O2 mixture (78/22 or 65/35%), time to the frst since patients’ characteristics and the evaluated interven- NIV session and its duration, total duration of He/O2 tion are similar in all studies. To assess publication bias, Abroug et al. Ann. Intensive Care (2017) 7:59 Page 3 of 11 we visually examined the funnel plot for NIV failure and Quality assessment performed the Egger test of the intercept which uses pre- Te three studies were randomized, controlled, non- cision to predict the standardized efect. All statistical blinded studies. Te risk of bias regarding random tests were two-sided. sequence generation and allocation concealment was low Te meta-analysis was conducted using the Com- in the study by Maggiore et al. [21] and unclear in the prehensive Meta-Analysis (CMA) program version 2 remaining two.