Noninvasive Mechanical Ventilation with Average Volume-Assured Pressure Support versus BiPAP S/T in De Novo Hypoxemic Respiratory Failure

Background Bilevel positive airway pressure in spontaneous/time and average volume-assured pressure support (BiPAP·S/T–AVAPS) could maintain an adequate tidal volume by reducing the patient's inspiratory effort; however, this ventilatory strategy has not been compared with other ventilatory modes, especially the conventional BiPAP S/T mode, when noninvasive mechanical ventilation (NIMV) is used. The primary objective of this study was to determine the rate of success and failure of the use of BiPAP·S/T-AVAPS versus BiPAP·S/T alone in patients with mild-to-moderate “de novo” hypoxemic respiratory failure. Methods This was a matched-cohort study. Subjects with mild-to-moderate de novo hypoxemic respiratory failure were divided into two groups according to the ventilatory strategy used. The subjects in the BiPAP·S/T group were paired with those in the BiPAP·S/T-AVAPS group. Results A total of 58 subjects were studied. Twenty-nine subjects in the BiPAP·S/T group were paired with 29 subjects in the BiPAP·S/T-AVAPS group. Twenty patients (34.5%) presented with “failure of NIMV,” while 38 (65.5%) patients did not. In addition, 13 (22.4%) patients died, while 45 (77.6%) recovered. No differences were found in the percentage of intubation (P=0.44) and mortality (P=0.1). Conclusion The BiPAP S/T-AVAPS ventilator mode was not superior to the BiPAP·S/T mode. A high mortality rate was observed in patients with NIMV failure in both modes. This trial is registered with https://doi.org/10.1186/ISRCTN17904857.


Background
Noninvasive mechanical ventilation (NIMV) is an effective treatment for pulmonary insufficiency with acute respiratory failure of various etiologies [1,2]. Regarding the use of NIMV in patients with acute respiratory failure (ARF), continuous positive airway pressure (CPAP) and bilevel positive airway pressure (BiPAP) have traditionally been chosen depending on the clinical condition, underlying disease, and severity of patients [3,4]. e ventilatory strategy, bilevel positive airway pressure in spontaneous/time and average volume-assured pressure support (BiPAP·S/T-AVAPS), allows the use of a fixed preprogrammed tidal volume (TV), which is kept constant by virtue of inspiratory pressure variations [5]. is ventilatory strategy estimates the delivered volume and adjusts its parameters to ensure a predetermined "target volume" [6].
e initial information about the use of BiPAP·S/T-AVAPS was focused on patients with chronic respiratory diseases, obstructive sleep apnea, or alveolar hypoventilation [7,8]. However, in our prior study, in case of ARF, a rapid sensory recovery was observed with the early use of this ventilatory strategy in patients with exacerbations of chronic obstructive pulmonary diseases (COPD) [9]. Subsequently, other authors have also observed similar results when BiPAP·S/ T-AVAPS was used in patients with exacerbated COPD [10,11].
We evaluated the BiPAP·S/T-AVAPS mode in patients with de novo hypoxemic respiratory failure and observed that it provides a better approach to protective ventilation in a selected group of subjects with mild-to-moderate hypoxemic respiratory insufficiency and spontaneous breathing to control the exhaled TV and inspired pressures [12].
It is now known that high exhaled TV and inspired airway pressure during NIMV use cause alterations in the bioelasticity of the respiratory system with lung damage. erefore, to avoid acute lung injury, an optimal ventilatory option is used to limit both the exhaled TV and inspired pressure. At present, this strategy, although described in patients with hypoxemic respiratory failure, has not been compared with other ventilatory modes, especially the conventional mode of BiPAP·S/T when using NIMV.
ere is a lack of information and research studies that compare the efficacy of the new ventilatory modes used in NIMV, specifically the ventilatory strategy with BiPAP·S/T-AVAPS, in the management of patients with ARF, making this topic attractive and novel.
is study was designed to compare the results of the use of guaranteed volume support pressure BiPAP·S/T-AVAPS versus BiPAP·S/T alone in patients with mild-to-moderate de novo hypoxemic respiratory failure. e primary objective was to compare the rate of rescue intubation between the two different modes. Secondary outcomes were days of NIMV, ICU stay, hospital stay, and mortality. A total of 58 patients were recruited in this study, and patients were divided into two groups according to the ventilatory strategy used: 29 in the BiPAP·S/T-AVAPS group and 29 in the control group (BiPAP·S/T alone). e person responsible for the decision to participate in the study was the patient or surrogate if he/she was not capable of making the decision. e study was conducted based on CONSORT regulations (https://doi.org/10.1186/ISRCTN17904857).

Study
is was a prospective study; for each patient treated with BiPAP·S/T-AVAPS, one matched control was selected, according to the following matching criteria: cause of ARF, severity of illness on admission within assessment score of acute physiology and chronic health evaluation (APACHE II) 5 points, age difference ≤5 years, ratio of partial arterial oxygen pressure and inspired fraction of oxygen (PaO 2 / FiO 2 ) within 10 points of the value of the treated group, and partial pressure of carbon dioxide (pCO 2 ) within 5 points. e matched group was selected from a consecutive database of patients previously treated with BiPAP S/T in our intensive care units (ICUs).
NIMV was administered on the first day for 24 h according to patients' tolerability. When NIMV was suspended, patients received oxygen through a mask connected to an oxygen reservoir having an FIO 2 of 0.5 to 0.6, for the shortest possible time. NIMV was restored as soon as patients' pulse oximetry SO 2 reached 90% or less.

Exclusion Criteria.
Participants were excluded based on the following criteria: (1) patients with facial deformity; (2) obstruction of the upper airway by surgery or trauma; (3) alterations in the central nervous system not related to hypercapnic encephalopathy; (4) cardiogenic pulmonary edema, pulmonary embolism, pneumothorax, hemoptysis, or septic shock; (5) urgent intubation due to cardiorespiratory arrest and hemodynamic instability with systolic pressure (SBP) < 80 mmHg; (6) if they demonstrated hemodynamic instability or excess respiratory secretions; (7) if they did not cooperate or were agitated or could not use the device interface; (8) if the patient had recently undergone upper airway surgery; and (9) if the patient had received NIMV with "Do Not Resuscitate" order.  Critical Care Research and Practice

Ventilatory Strategy in BiPAP S/T Mode.
Ventilatory parameters initially programmed in the S/T mode were as follows: IPAP, 12-20 cmH 2 O, according to the physician's assessment; EPAP, 6 cmH 2 O; rRR, 15 breaths/min; rise time, 300-400 ms; and inspiratory time, 0.6-1.2 s. e IPAP was progressively augmented with 2 cmH 2 O, according to the prescription of the attending physician. Oxygen supplements were added through an O 2 adapter close to the mask to maintain the SaO 2 above 90%. e exhaled current volume (EVT), Vmin, and leakage were controlled using a ventilator software. e synchronization of BiPAP with AVAPS was carried out using Auto-Trak (Respironics Inc. Murrysville. Pennsylvania. USA), a series of Mirage IV (Resmed) masks, and a Confourt Series II mask (Respironics).

Measurements.
Arterial blood gases (ABG) were measured at baseline and 1, 12, and 24 h after the use of NIMV. Patients were evaluated by a respiratory therapist under strict supervision of the physician trained in NIMV. Complications of mask use were reported, if any. e severity of the disease was assessed by the APACHE II score. Maximum programmed VT, maximum patient IPAP, exhaled tidal volume, Vmin, leakage, RR of the patient, and IPAP were reported at baseline and during the first 48 h of NIMV obtained in the early morning hours. e mask use and tolerability were also evaluated. e tolerance capacity of the mask (comfort score) was evaluated as follows: 1 � low, 2 � average, and 3 � good [15]. Complications inherent to the use of the technique, including abdominal distension, skin necrosis, epistaxis, and ear pain, were also evaluated [16].
2.9. Discontinuation of NIMV. NIMV was initially used continuously in accordance with the patients' tolerance until the PaO 2 /FiO 2 ratio was above 400 mmHg, and the decision of the medical staff considered a partial or total resolution of the cause that led to receiving NIMV. e weaning process was initiated when clinical stability was achieved, which was defined as an RR less than 25 resp/min, a heart rate (HR) of 100 beats/minute, improvement in the level of consciousness, compensation of the pH, ambient air with SaO 2 > 90%, or a low rate of FiO2 (3 L/min). NIMV was discontinued when the patient remained stable for >24 hours.

Outcome
Measures. e primary outcome was success or failure of NIMV (requirement for endotracheal intubation). e secondary outcomes were ICU duration of hospitalization and mortality.

Calculation of Sample Size.
In this study, to detect a 20% difference between success and failure of NIMV between the two groups with a Type I error of 0.05 (Alpha significant) and a Type II error of 0.20 (Beta, 1-power), sixty patients (30 in each group) were required. All data are expressed as mean ± standard deviation (SD) for continuous variables and percentages for categorical variables. Normally distributed continuous variables were determined using the Kolmogorov-Smirnov test and were compared using Student's t-test. For nonparametric distribution variables, the chi-square or Fisher's exact test was used, depending on the case. e NIMV results were compared between the two groups. Statistical significance was set at P value < 0.05.

Results
A total of 58 subjects were studied (29 subjects in the BiPAP S/T group were paired with 29 subjects in the BiPAP·S/T-AVAPS group) (Figure 1). e average age of the study  Table 1.
No differences were found between the BiPAP·S/T and BiPAP·S/T-AVAPS groups ( Table 2).

Discussion
In this study, we found no differences in the outcomes of BiPAP·S/T-AVAPS versus BiPAP·S/T alone in patients with "de novo" hypoxemic respiratory failure.
ere were no differences in the percentage of intubation or mortality in either group, or in the duration of IMV, hospital stay, or ICU stay. To our knowledge, this study is the first to compare the two ventilatory strategies in this subgroup of patients with de novo hypoxemic respiratory failure.
BiPAP·S/T-AVAPS has been shown to be useful in patients with hypercapnic ARF, especially in obstructive pulmonary disease and alveolar hypoventilation [17]. Other studies have shown the advantages of this method in patients with hypercapnia, especially by guaranteeing TV and minute ventilation and decreasing the percentage of intubation compared with conventional BIPAP·S/T [9,11]. Additionally, AVAPS facilitates successful extubation in ARDS [18].
Current therapeutic options for hypoxemic ARF are limited and mainly focus on minimizing ventilator-induced  Critical Care Research and Practice lung injury (VILI) [19]. It is now known that it is difficult to maintain a low expiratory TV in patients who are receiving NIMV for hypoxemic ARF, which is generally associated with NIMV failure [20]. Studies have shown that high TV is a predictor of NIMV failure, especially in patients with ARF and moderate-to-severe hypoxemia [21]. High inspired pressures with high ETVs were observed in most patients in whom the AVAPS ventilatory strategy failed. In addition, the use of low TVs with limited airway pressure is essential for lung protection. In some cases, especially in patients with hypoxemic respiratory failure, an excessive increase in inspired pressure could increase intrathoracic pressure and reduce venous return. Moreover, the cardiac index decreases at high inspired pressures [22].
AVAPS attempts to maintain an adequate TV by decreasing the inspiratory effort of the patient and increasing the programmed pressure automatically without exceeding the programmed maximum IPAP when the preset TV is not reached [23]. We found a high mortality rate in patients in whom NIMV failed. Furthermore, an increase in mortality due to delayed intubation in patients with NIMV is well documented [24]. However, we did not observe differences in the failure of NIMV between the BiPAP·S/T-AVAPS and BiPAP·S/T groups.  Our study had the following limitations: (1) it is a "single-center" study and not a randomized controlled trial; (2) other types of interfaces used in de novo respiratory failure NIMV, such as helmet systems that tolerate high levels of positive end-expiratory pressure, have not been evaluated; (3) the majority of these patients were diagnosed with community-acquired pneumonia; therefore, the results could not be extrapolated to hypoxemic respiratory failure of another etiology; (4) the effect of the learning curve could influence the results because our results were obtained in two ICUs with staff having extensive NIMV experience and familiarity with the use of the AVAPS ventilatory strategy, which should be considered when generalizing the results to other centers with less experience.
Nevertheless, we believe that this study provides important data, as this is the first study to evaluate these two ventilatory modes of BiPAP·S/T-AVAPS vs. BiPAP·S/T alone in patients with "de novo" hypoxemic respiratory failure. However, a large-scale randomized controlled study is necessary to assess and compare this approach with other strategies such as continuous high-flow nasal oxygen therapy [25].

Conclusion
e results of this study suggest that BiPAP·S/T-AVAPS can be used in patients with ARF. Patients with hypercapnic ARF had a greater positive response to a ventilation strategy with BiPAP·S/T-AVAPS than those with de novo hypoxemic ARF. BiPAP·S/T-AVAPS mode ventilators were not superior to the conventional NIMV mode BiPAP·S/T. A high percentage of mortality was observed in patients with failure of NIMV in both modes, especially "de novo" respiratory hypoxemic failure.

abrARF:
Acute respiratory failure S: Spontaneous S/T: Spontaneous/time BiPAP S/T-AVAPS: Bi-level positive airway pressure in spontaneous/time and guaranteed support pressure with medium volume BiPAP S/T: Bi-level positive airway pressure in spontaneous/time PaO2/FiO2: Ratio of partial arterial oxygen pressure and inspired fraction of oxygen FiO2: Inspired fraction of oxygen EVT: Exhaled tidal volume Vmin: Volume per minute TV: Tidal volume ARDS: Acute respiratory distress syndrome SBP: Systolic blood pressure DBP: Diastolic blood pressure HR: Heart rate RR: Respiratory rate ABGs: Arterial blood gas pH: e negative algorithm of the hydrogen ion concentration SaO2: Arterial oxygen saturation PO2: Partial pressure of arterial oxygen PCO2: Partial pressure of carbon dioxide EB: Excess base IPAP: Inspiratory positive airway pressure EPAP: Expiratory positive airway pressure APACHE II: Assessment score of acute physiology and chronic health evaluation SD: Standard deviation COPD: Chronic obstructive pulmonary disease NIMV: Noninvasive mechanical ventilation IT: Inspiratory time RAMP: Time to change from the expiratory pressure to the inspiratory pressure setting.
Data Availability e datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Ethical Approval
Appropriate written informed consent was obtained for the publication of this case report and the accompanying images.

Consent
A copy of the written consent is available for review by the Editor-in-Chief of the journal.

Conflicts of Interest
e authors declare that they have no conflicts of interest.

Authors' Contributions
KHBC was responsible for conceptualization, data curation, formal analysis, funding acquisition, investigation