|Year : 2015 | Volume
| Issue : 2 | Page : 34-42
Adaptive support ventilation versus biphasic positive airway pressure in patients with acute exacerbation of chronic obstructive pulmonary disease
Amr A Elmorsy, Bassem N Beshay, Emad H Mousa
Department of Critical Care Medicine, Faculty of Medicine, Alexandria University, Alexandria, Egypt
|Date of Submission||26-Dec-2014|
|Date of Acceptance||04-Mar-2015|
|Date of Web Publication||30-Dec-2016|
Bassem N Beshay
Department of Critical Care Medicine, Faculty of Medicine, Alexandria University, Alexandria
Source of Support: None, Conflict of Interest: None
The goal of mechanical ventilation in acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is to maintain both adequate oxygenation and ventilation, reduce the work of breathing, and improve the comfort of the patient until the condition has been reversed or alleviated. Unlike conventional pressure-controlled ventilatory modes, biphasic modes [biphasic positive airway pressure (BIPAP)] allow for unrestricted spontaneous breathing. Adaptive support ventilation (ASV) is a new ventilatory mode that uses a closed-loop controlled mode between breaths. It can be used safely during initiation, maintenance, or weaning phases of the mechanical ventilation.
The aim of this work was to compare between BIPAP and ASV in the management of patients with AECOPD in terms of ventilatory parameters, lung mechanics, patient ventilator dys-synchrony, days of mechanical ventilation, and mortality.
Patients and methods
This double-blind randomized trial was conducted on 72 AECOPD adult patients admitted to the units of Critical Care Medicine Department in Alexandria Main University Hospital indicated for invasive mechanical ventilation. Patients were excluded for reasons such as pregnancy, hemodynamic instability, and severe neurological disease. They were categorized randomly as follows: group I included 36 patients who were ventilated using the BIPAP mode and group II included 36 patients who were ventilated using the ASV mode. Informed consent was obtained from patients' first of kin after approval from the Ethical Committee of Alexandria Faculty of Medicine. Ventilatory parameters (respiratory rate, tidal volume, peak airway pressure, and rapid shallow breathing index) and lung mechanics (static compliance and inspiratory resistance) were recorded. Patient ventilator dys-synchrony and asynchrony index were recorded daily. Days of mechanical ventilation, ICU stay, and mortality were calculated.
In the ASV group, the respiratory rate was significantly lower, tidal volume was higher, and rapid shallow breathing index was lower. Significantly higher compliance and lower resistance were encountered in the ASV group, with better patient-ventilator synchronization. A significant reduction in days of mechanical ventilation in the ASV group was found with less ICU length of stay.
ASV may be safer in AECOPD patients and may have a better prognosis.
Keywords: Acute exacerbation of chronic obstructive pulmonary disease, adaptive support ventilation, biphasic positive airway pressure
|How to cite this article:|
Elmorsy AA, Beshay BN, Mousa EH. Adaptive support ventilation versus biphasic positive airway pressure in patients with acute exacerbation of chronic obstructive pulmonary disease. Res Opin Anesth Intensive Care 2015;2:34-42
|How to cite this URL:|
Elmorsy AA, Beshay BN, Mousa EH. Adaptive support ventilation versus biphasic positive airway pressure in patients with acute exacerbation of chronic obstructive pulmonary disease. Res Opin Anesth Intensive Care [serial online] 2015 [cited 2017 Oct 17];2:34-42. Available from: http://www.roaic.eg.net/text.asp?2015/2/2/34/161325
| Introduction|| |
An acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is characterized by a worsening of the patient's progressive airflow limitation that is beyond normal day-to-day variation and leads to a change in medications .
In-hospital mortality of patients admitted for AECOPD is ~10%. Mortality reaches 40% at 1 year after discharge in those needing mechanical support and all-cause mortality 3 years after hospitalization is as high as 49% ,.
AECOPD can be precipitated by several factors. The most common cause appears to be respiratory tract infection. Air pollution can also precipitate exacerbations of chronic obstructive pulmonary disease (COPD). However, the cause in about one-third of patients cannot be identified .
Treatment options of AECOPD include pharmacological therapy (bronchodilators, intravenous methylxanthines, corticosteroids, and antibiotics) and respiratory support (oxygen therapy and ventilatory support by noninvasive or invasive positive pressure ventilation) .
Invasive positive pressure ventilation is indicated in AECOPD in different situations; for example, respiratory or cardiac arrest, diminished consciousness, massive aspiration, persistent inability to remove respiratory secretions, severe hemodynamic instability without response to fluids or vasoactive drugs, severe ventricular arrhythmias, and life-threatening hypoxemia in patients who cannot tolerate noninvasive ventilation .
The main objective of mechanical ventilation is to maintain both adequate oxygenation and ventilation; it reduces the work of breathing (WOB) and improves the comfort of the patient until the condition that forced the need for this technique has been reversed or alleviated. In an effort to fulfill these objectives, a variety of ventilatory modes have been developed that can potentially reduce complications, shorten the duration of mechanical ventilation, and thus improve clinical outcomes .
Traditional volume modes of ventilation, most notably assist control and synchronized intermittent mandatory ventilation (SIMV), although still used widely are becoming less popular. In contrast, pressure modes were initially configured to ensure that a clinician-selected inspiratory pressure level (IPL) was provided on a breath-to-breath basis; the volume varied with each breath. All pressure modes are associated with a 'decelerating' flow pattern during inspiration that is considered more physiologic than that associated with volume-based ventilation and may contribute toward better gas distribution ,.
Biphasic modes are similar to pressure control ventilation (PCV) in that the clinician selects IPL and positive end-expiratory pressure (PEEP) levels as well as frequency (fx) and inspiratory time (Ti). However, unlike conventional PCV, these modes allow for unrestricted spontaneous breathing during the I/E cycles. Parameters for setting biphasic modes vary between ventilators, but include PEEP high (PEEP H ), PEEP low (PEEP L ), fx, and Ti. If additional support is desired for patient-initiated breathing, pressure support (P SUPP ) may be selected as well ,.
Adaptive support ventilation (ASV) is a new ventilatory mode that uses a closed-loop controlled mode between breaths. The ventilator allows the clinician to set a maximum plateau pressure and desired minute ventilation on the basis of the patient's ideal weight. It automatically selects the target ventilatory pattern on the basis of user inputs, as well as taking into account the respiratory mechanics data from the ventilator monitoring system (resistance, compliance, auto-PEEP). Thus, this mode can be used safely during initiation, maintenance, or weaning phases of the mechanical ventilation. ASV's goal is to ensure an effective alveolar ventilation level, minimizing the WOB, and leading the patient to an optimal ventilatory pattern to reduce complications such as volutrauma or barotrauma and air trapping .
| Objectives|| |
The aim of this work was to compare between biphasic positive airway pressure (BIPAP) and ASV in the management of patients with AECOPD in terms of the following:
- Ventilatory parameters.
- Lung mechanics.
- Patient ventilator dys-synchrony including:
- Flow dys-synchrony.
- Cycling dys-synchrony.
- Trigger dys-synchrony.
- Days of mechanical ventilation.
- Mortality on day 7 and 28.
| Patients and methods|| |
This double-blind randomized trial was conducted on 72 consecutive adult patients, according to sample size calculation, who were admitted to the units of Critical Care Medicine Department in Alexandria Main University Hospital with the diagnosis of AECOPD and indicated for invasive mechanical ventilation. Patients were excluded for reasons such as pregnancy, hemodynamic instability, and severe neurological disease hindering the respiratory drive. Patients were categorized randomly using the closed-envelope method into two groups:
- Group I: included 36 patients who were mechanically ventilated using the BIPAP mode.
- Group II: included 36 patients who were mechanically ventilated using the ASV mode.
Informed consent was obtained from first-degree relatives of every patient included in the study. The research was approved by the Ethical Committee of Alexandria Faculty of Medicine. All selected patients fulfilling the inclusion criteria were subjected to the following on admission: full assessment of history, clinical examination, complete chest examination, and a plain bedside anteroposterior chest radiography. Routine ICU investigations were performed on admission and when needed so that any abnormal values were corrected.
Arterial blood gas samples were withdrawn for all patients on admission and when needed as long as patients were mechanically ventilated. During the ICU stay, all patients were managed according to standard protocols of the management of AECOPD patients .
All patients were ventilated mechanically using the volume A/C mode for the first 2 h, during which we recorded the following: (a) ventilatory parameters: including respiratory rate, tidal volume, peak airway pressure, and rapid shallow breathing index (RSBI) (respiratory rate/tidal volume). (b) Lung mechanics: including static compliance and inspiratory resistance. After the first 2 h, the studied patients (72 patients) were serially randomized into two groups:
- Group I: included 36 patients who were mechanically ventilated through the BIPAP mode using a microprocessor-controlled mechanical ventilator (Galileo GOLD; Hamilton Medical AG, Bonaduz, Switzerland).
- Group II: included 36 patients who were mechanically ventilated through the ASV mode using a microprocessor-controlled mechanical ventilator (Galileo GOLD; Hamilton Medical AG).
Ventilatory parameters were adjusted in both groups according to arterial blood gas analysis to reach their premorbid CO 2 with better oxygenation parameters in such COPD patients for better weaning conditions. The following parameters were monitored during the patients' entire stay in ICU and recorded every 12 h: vital signs (heart rate and mean arterial blood pressure), arterial blood gases, ventilatory parameters (respiratory rate, tidal volume, peak airway pressure, and RSBI), and lung mechanics (static compliance and inspiratory resistance). For the measurement of lung mechanics, patients were switched to the A/C volume mode once daily for 10 min.
Patient ventilator dys-synchrony was monitored and recorded daily. It included flow, cycling, and triggering dys-synchrony. The asynchrony index (AI) was calculated. It is defined as the percentage of asynchronous to total breaths during the recording period . The primary end-point of the study was days of mechanical ventilation, whereas 7- and 28-day mortality was the secondary end-point.
Statistical analysis of data
Data were analyzed using the IBM SPSS software package, version 20.0 (SPSS, Chicago, IL, USA). Qualitative data were described as number and percent. Quantitative data were described as mean, SD, median, minimum, and maximum. Comparison between different groups of categorical variables was tested using the χ2 -test. When more than 20% of the cells had an expected count less than 5, correction for χ2 was performed using Fisher's exact test or Monte Carlo correction.
The distributions of quantitative variables were tested for normality using the Kolmogorov-Smirnov test, the Shapiro-Wilk test, and the D'Agstino test; also, histogram and QQ plot were used for vision test. If it showed a normal data distribution, parametric tests were applied. If the data were abnormally distributed, nonparametric tests were used. For normally distributed data, comparison between two independent populations was carried out using an independent t-test. For abnormally distributed data, comparison between two independent populations was carried out using the Mann-Whitney test. Significance test results are quoted as two-tailed probabilities. The significance of the obtained results was judged at the 5% level.
| Results|| |
Demographic data of the patients
Both groups were matched in age and sex without statistically significant differences between them [Table 1].
|Table 1 Comparison between the two groups studied according to demographic data|
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0On day 1, the mean respiratory rate (cycles/min) in group I was 22.42 ± 2.73 and 21.92 ± 3.45 in the day and in the night, respectively, and this was significantly higher than that in group II, in which the mean respiratory rate in the day and in the night was 20.58 ± 1.68 and 19.83 ± 1.42, respectively. P = 0.001) for day time and P = 0.002 for night time [Figure 1].
|Figure 1: Comparison between the two groups studied according to the respiratory rate. The mean respiratory rate was measured in cycles/ min. ASV, adaptive support ventilation; BIPAP, biphasic positive airway pressure.|
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On day 2, the mean respiratory rate in group I in the day and in the night (19.25 ± 2.72 and 19.30 ± 3.25) was again significantly higher than that in group II (17.33 ± 1.62 and 16.30 ± 2.04) (P = 0.001).
On day 1, the mean tidal volume (ml/kg) in group I was 6.35 ± 1.45 and 6.73 ± 1.72 in the day and in the night, respectively, and this was significantly lower than that in group II, in which the mean tidal volume in the day and in the night was 7.90 ± 0.69 and 8.45 ± 0.63, respectively (P < 0.001) [Figure 2].
|Figure 2: Comparison between the two groups studied according to Vt/kg. The mean tidal volume was measured in ml/kg. ASV, adaptive support ventilation; BIPAP, biphasic positive airway pressure.|
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On day 2, the mean tidal volume in group I in the day and in the night (7.41 ± 1.46 and 7.17 ± 1.44) was again significantly lower than that in group II (8.65 ± 0.69 and 8.66 ± 0.59) (P < 0.001).
Peak inspiratory pressure
On day 1, the mean peak inspiratory pressure (PIP) (cmH 2 O) in the day in group I (31.75 ± 3.75) was significantly lower than that in group II (36.50 ± 2.25) (P < 0.001). In the night, the mean PIP in group I (31.08 ± 5.37) was nonsignificantly lower than that in group II (32.92 ± 4.02) (P = 0.106) [Figure 3].
|Figure 3; Comparison between the two groups studied according to the peak inspiratory pressure (PIP). The mean PIP was measured in cmH2O. ASV, adaptive support ventilation; BIPAP, biphasic positive airway|
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On day 2, the mean PIP did not show significance in groups I and II in the day (29.08 ± 4.73 and 30.83 ± 3.70) and in the night (29.80 ± 4.68 and 28.80 ± 2.44) (P = 0.085 and 0.305, respectively).
Rapid shallow breathing index
On day 1, the mean RSBI in group I was 57.09 ± 31.72 and 57.09 ± 31.72 in the day and in the night, respectively, and this was significantly higher than that in group II, in which the mean RSBI in the day and in the night was 41.75 ± 8.88 and 36.08 ± 4.29, respectively (P < 0.001) [Figure 4].
|Figure 4: Comparison between the two groups studied according to RSBI. ASV, adaptive support ventilation; BIPAP, biphasic positive airway pressure; RSBI, rapid shallow breathing index.|
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On day 2, the mean tidal volume in group I in the day and in the night (42.18 ± 12.79 and 44.20 ± 18.44) was again significantly higher than that in group II (30.83 ± 4.91 and 29.20 ± 4.45) (P < 0.001).
On day 1, the mean static compliance (ml/cmH 2 O) in group I (40.33 ± 5.96) was significantly lower than that in group II (43.67 ± 3.64) (P = 0.006). On day 2, the mean lung compliance in group I (45.0 ± 5.07) was also significantly lower than that in group II (49.58 ± 3.25) (P = 0.001) [Figure 5].
|Figure 5: Comparison between the two groups studied according to static compliance. Mean static compliance was measured in ml/cmH2O. ASV, adaptive support ventilation; BIPAP, biphasic positive airway|
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On day 1, the mean inspiratory resistance (cmH 2 O/l/s) in group I was 5.88 ± 2.34 whereas in group II, it was 6.08 ± 2.71. This difference was not significant (P = 0.728). On day 2, the mean inspiratory resistance in group I (4.67 ± 1.54) was insignificantly higher than that in group II (4.30 ± 1.80) (P = 0.360). On day 3, the mean inspiratory resistance in group I (5.81 ± 2.34) was significantly higher than that in group II (3.0 ± 0.0) (P = 0.033) [Figure 6].
|Figure 6: Comparison between the two groups studied according to inspiratory resistance. ASV, adaptive support ventilation; BIPAP, biphasic positive airway pressure.|
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In the first 2 h, when patients were sedated and mechanically ventilated using the volume control mode; 86.1% of patients in group I and 91.7% of patients in group II did not have dys-synchrony, without any significant difference between them ( MCP = 0.836) [Table 2].
|Table 2 Comparison between the two groups studied according to dys-synchrony|
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On day 1, 55.6% of patients in group I and 75% of patients in group II did not have dys-synchrony; however, this difference was not statistically significant (χ2P = 0.383). On day 2, only 63.9% of patients in group I did not have dys-synchrony versus 97.3% of patients in group II who did not show any dys-synchrony. The difference between both groups was highly significant ( FEP = 0.005).
On day 1, the number of patients who had AI more than 10 in group I was seven versus one patient in group II. This was statistically significant (χ2P = 0.024). On day 2, six patients in group I had AI more than 10 versus no patient in group II. Again, this was statistically significant ( FEP = 0.025) [Table 3].
|Table 3 Comparison between the two groups studied according to the asynchrony index|
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Duration of mechanical ventilation
The mean days of mechanical ventilation in group I was 5.36 ± 1.22, which was significantly higher than that in group II (3.50 ± 0.65) ( MWP < 0.001). In group I, 15 patients required noninvasive positive pressure ventilation after they were extubated, with a mean of 1.13 ± 0.70 days, and this was significantly higher than that in group II, in which eight patients only required noninvasive positive pressure ventilation after extubation with a mean of 0.51 ± 0.19 days ( MWP = 0.007) [Table 4].
|Table 4 Comparison between the two groups studied according to days of MV (NIMV and invasive MV)|
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ICU length of stay
The mean ICU length of stay in group I was 7.08 ± 0.64 days. In group II, it was 4.15 ± 0.82 days. The difference between both groups was statistically significant (P = 0.006) [Table 5].
|Table 5 Comparison between the two groups studied according to ICU length of stay|
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In terms of mortality, on day 7, one patient died in group I versus no one in group II. The 28-day mortality was four and five patients in both groups, respectively. This was not statistically significant (P = 1.000) [Table 6].
|Table 6 Comparison between the two groups studied according to mortality|
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| Discussion|| |
BIPAP has become one of the frequently used modes for the management of AECOPD patients. In a study carried out by Sen  on chronic obstructive lung patients undergoing major abdominal surgery for early extubation, he compared two modes, namely, biphasic-level positive airway pressure and pressure SIMV. He concluded that BIPAP prevents dynamic airway collapse, led to better patient compliance, earlier extubation time, and reduced the possibility of re-intubation.
ASV combines various ventilatory modes: PSV, if the patient's respiratory rate is higher than the target, PCV, if there is no spontaneous breathing; and SIMV, when the patient's respiratory rate is lower than the target. This has led many authors to call it the 'no mode' or the 'integrated mode' .
To date, no single study had compared between BIPAP and ASV or even used ASV as a management mode in AECOPD patients. Arnal et al. , in their study, highlighted the ability of ASV to adjust the tidal volume-respiratory frequency combination according to respiratory mechanics, detect the patient's spontaneous respiratory rate to adjust the ventilatory support accordingly, limit intrinsic PEEP, and reduce weaning time.
In the present study, three of the four ventilatory parameters recorded, namely, respiratory rate, tidal volume, and RSBI, were significantly better with the ASV mode than the BIPAP mode.
In a study carried out by Belliato et al. , ASV was tested in patients with different clinical conditions, of whom eight patients had AECOPD. They were intubated, sedated, paralyzed, and subjected to total controlled mechanical ventilation for respiratory failure. ASV selected a high expiratory time pattern, with the selection of very low respiratory rates, up to 6-8 beats/min. Moreover, during the study, it was observed that these patients had almost clinically negligible low values of auto-PEEP. They assumed that the respiratory mechanics analysis in COPD patients carried out by ASV, characterized by low rate and high tidal volume, seems to be as correct as the strategies used commonly in the clinical setting with low tidal volume. The authors explained that ASV would select an adequate ventilatory pattern and adjust according to the patient's mechanics.
Another study, which was a prospective crossover interventional multicenter trial, was carried out by Iotti et al.  to compare the short-term effects of ASV with conventional volume or PCV in patients ventilated passively for acute respiratory failure. This study was carried out in six European academic ICU and included 88 patients in three groups: patients with no obvious lung disease (n = 22), restrictive lung disease (n = 36), or obstructive lung disease (n = 30). After measurements on conventional ventilation (CV) as set by the patients' clinicians, each patient was switched to ASV to obtain the same minute ventilation as during CV (isoMV condition). If this resulted in a change in PaCO 2 , the minute ventilation setting of ASV was readjusted to achieve the same PaCO 2 as in CV (isoCO 2 condition). Compared with CV, PaCO 2 during ASV in the isoMV condition and minute ventilation during ASV in the isoCO 2 condition were slightly lower, with lower inspiratory work/min performed by the ventilator (p0.01). Oxygenation and hemodynamics were unchanged. During ASV, the respiratory rate was slightly lower and tidal volume (Vt ) was slightly higher, especially in COPD patients. During ASV, there were different ventilatory patterns in the three groups, with lower Vt in patients with restrictive disease and prolonged expiratory time in obstructed patients, thus mimicking the clinicians' choices for setting CV.
Higher static lung compliance and lower inspiratory resistance were significantly noted with the ASV mode of ventilation than the BIPAP mode in the present study. Of note also was the better patient-ventilator synchronization in the ASV group as noted by the marked decrease in all types of dys-s ynchrony as well as significantly lower AI than the BIPAP group of patients.
In a study carried out by Tasseaux et al. , which was a crossover prospective study in the early weaning period of 10 patients with acute respiratory failure of diverse causes, the objective was to compare the effects of ASV with the effects of SIMV plus pressure support (SIMV-PS) on patient-ventilator interactions in patients undergoing partial ventilatory support. In three patients, the cause of acute respiratory failure was AECOPD. The results showed that at a similar level of minute ventilation, patients receiving ASV had a lower level of respiratory drive (P0.1 ), lower WOB (on the basis of electromyography respiratory muscle activity), and improved patient-ventilator interactions compared with SIMV-PS. The authors concluded that in patients with increased respiratory muscle loading and for comparable minute ventilation, ASV was associated with decreased inspiratory load and improved patient-ventilator interactions.
Another study was carried out by Wysocki and Brunner  to compare the effect of ASV and conventional volume control mode on respiratory mechanics. The study that was carried out on thirteen patients with ALI/ARDS and found that with conventional mechanical ventilation, the ventilator mode is selected and then the parameters are controlled depending on changes in the patient's condition. In contrast, in the ASV mode, the ventilator settings change automatically, such as from the PCV-like mode to either the SIMV-like or the PSV-like mode. In this study, the ASV mode lung parameters were collected to verify whether ASV could be applied to patients who have severe lung disease, such as ALI/ARDS, and the results were compared with those of a conventional ventilator mode. The 13 ALI/ARDS patients subjected to the ASV mode had a lower peak airway pressure compared with the VCV mode and greater compliance and tidal volume. Therefore, the lung mechanics showed overall improvement.
The present study showed a significant reduction in days of mechanical ventilation in the ASV group and those weaned needed less noninvasive ventilation. This was reflected on the ICU length of stay, which was significantly less in the ASV group. Seven- and 28-day mortality was not significant in both groups.
In agreement with our study in terms of period of mechanical ventilation, Sultzer et al.  tested the hypothesis that a protocol of respiratory weaning on the basis of ASV could reduce the duration of tracheal intubation after uncomplicated cardiac surgery. The study was carried out on 49 patients; 36 completed the weaning protocol and were included in the statistical analysis. A group of patients administered ASV was compared with a control group (on the basis of SIMV with PS) in a randomized-controlled study. The primary outcome of the study, the duration of tracheal intubation, was shorter in the ASV group than in the control group. Fewer arterial blood analyses were carried out in the ASV group, suggesting that fewer changes in the settings of the ventilator were required in this group. They concluded that a respiratory weaning protocol on the basis of ASV is practical and may accelerate tracheal extubation and simplify ventilatory management in fast-track patients after cardiac surgery.
Similarly, Cassina et al.  carried out a prospective observational study of a cohort of 155 consecutive patients after fast-track cardiac surgery, and confirmed the safety aspects of ASV. As the study was by design observational and as such did not enable any comparison with other ventilatory strategies, its main aim was to assess the feasibility of a weaning protocol based on an automatic ventilation mode. A total of 134 patients (86%) were extubated within 6 h. No reintubation because of respiratory failure was required. ICU length of stay was less than 48 h for 114 patients (74%). This ventilation mode enabled rapid extubation in suitable patients and may facilitate postoperative respiratory management.
In a more recent study carried out by Kirakli et al.  titled ASV for faster weaning in COPD: a randomized-controlled trial, 97 COPD patients admitted to ICU during a 20-month period were studied. Patients were assigned at random to either ASV or PSV as a weaning mode. Compared with PSV, they found that ASV provided shorter weaning times with similar weaning success rates. Length of stay in the ICU was also shorter with ASV, but the difference was not statistically significant. They suggested that ASV may be used in the weaning of COPD patients with the advantage of shorter weaning times.
| Conclusion|| |
ASV was associated with lower respiratory rate, larger tidal volume, lower RSBI, higher compliance, better patient-ventilator synchrony, reduction of ventilation days, and ICU length of stay when used in the management of patients with AECOPD.
| Acknowledgements|| |
Our deep gratitude is directed to our beloved late Professor Hassan Abdelaziz Abu-Khabar for his creation in choosing the idea of this work and his continuous support and indefinite encouragement.
Conflicts of interest
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]