The Effect of Preemptive APRV on Patients With High Risk for ARDS
The Effect of Preemptive APRV on Patients With High Risk for ARDS
Airway pressure release ventilation (APRV) is a mode of mechanical ventilation that
 alternates between two levels of continuous positive airway pressure (CPAP) support and
 allows spontaneous respiratory effort at either CPAP level. It is considered as an
 alternative, life-saving modality in patients with acute respiratory distress syndrome (ARDS)
 that struggle for oxygenation. Compared to the classical ventilation, APRV has been shown to
 provide lower peak pressure, better oxygenation, less circulatory loss, and better gas
 exchange without deteriorating the hemodynamic condition of the ARDS patient. This mode is
 believed to help to achieve the target of opening consolidated lung areas (recruitment) and
 to prevent repeated opening-closing of alveoli (decruitment). However, there is still
 insufficient and limited proof to support this hypothesis.

 Recently, it has been proposed that early use of protective mechanical ventilation with APRV
 could be used preemptively to prevent development of ARDS in high risk patients. In that
 study, APRV prevented clinical and histological lung injury by protecting alveolar epithelial
 integrity, preserving surfactant and alveolar stability, and reducing pulmonary edema.

 The primary purpose of the present study was to investigate whether early use of APRV as a
 lung-protecting strategy was superior to the conventional methods in a patient population
 with high risk of acute respiratory distress syndrome (ARDS).
This study was planned as a single-centered, prospective, and randomised-controlled study in
 a general intensive care unit with 18 bed capacity. The majority of the general patient
 population is made up of trauma and post-operative patients. The local ethics committee
 reviewed and approved the study protocol (protocol number: 2016/175) prior to the start of
 the investigation. Enrollment for the study was performed between May 2016-October 2018.
 Written informed consent was obtained from each patient's relatives.

 Study design and sample:

 The study included patients who required invasive mechanical ventilation but was not
 initially diagnosed with ARDS 9, had a LIPS (Lung Injury Prediction Score) of > 7 10, and
 have been staying in the ICU for more than 24 hours. Patient demographic properties, sedation
 requirements, inotrope/vasopressor levels, ARDS development status during follow-up,
 mechanical ventilation times, length of ICU stay, arterial blood gas results, mean airway
 pressure (Pmean), peak airway pressure (Ppeak) and tidal volume (Vt) in addition to the
 mode-specific mechanical ventilation parameters were recorded. Exclusion criteria were
 pregnancy, intracranial hypertension (suspected or confirmed by measurement with external
 ventricular drainage catheter), severe chronic obstructive pulmonary disease or type II
 respiratory failure, confirmed bronchopleural fistula, documented barotrauma, history of
 pneumonectomy, and age below 18 or above 85 years. Consecutive eligible patients were
 enrolled block randomization with a 1:1 allocation, randomly assigned to APRV or P-SIMV+PS
 groups using opaque, sealed envelopes.

 Ventilator Settings:

 All mechanical ventilation settings were made by intensivists, or trained residents on the
 night shifts. Prior to randomization, all patients were treated with VC-SIMV mode. Patients
 admitted during the day were ventilated in VC-SIMV mode until the main investigators
 evaluated the patient (1-2 hours), and patient admitted in the evening-night shift were
 ventilated in VC-SIMV mode until the main investigators took over the shift in the morning
 (maximum 16 hours). Assignment to groups was performed after calculation of LIPS score.
 Microprocessor-controlled mechanical ventilators (Galileo GOLD; Hamilton Medical AG, Bonaduz,
 Switzerland) and heated humidifiers were used as a standard in all patients. In both groups,
 mechanical ventilation targets were determined as maintaining plateau airway pressure
 (Pplateu) < 30 cmH2O and PaO2 between 60-100 mmHg or SO2>88%. In both groups, arterial blood
 gas measurement was performed at least twice a day. Oxygenation and respiratory mechanics
 were evaluated by comparing P-SIMV+PS and APRV groups at baseline and on days 1, 2, 3, and 7.
 Patients were followed until transfer to CPAP/T-tube and extubation, or a maximum of 28 days.
 During this period, follow-up was terminated once at extubation, exitus, discharge from ICU
 or ARDS occurred.

 P-SIMV+PS group:

 The reason behind using P-SIMV+PS as a conventional mode was that it is a pressure controlled
 mode like APRV. Pressure level was adjusted in order to get a Vt of 6-8 ml.kg-1.PBW-1
 (predicted body weight). Optimal PEEP between 5-10 cmH2O was applied to all patients by
 titrating according to O2 requirement. Respiratory rate was adjusted as 12-15 breaths.min-1,
 and inspiratory time was initially adjusted to approximately 1.5 seconds. The I:E ratio was
 adjusted by either changing inspiratory time, respiratory rate, or both. Inspiratory
 triggering sensitivity was adjusted as 2 L.min-1, and was tittered by reaching the minimum
 level in the absence of automatic triggering.

 APRV group:

 Standard initial settings were Thigh / Tlow: 4/0.8 secods, Phigh: taking Pplateau value (if
 patient is paralyzed) or Pmean in the previous conventional method as reference, Pplateau <
 30 cmH20 and target Vt 6-8 ml.kg-1.PBW-1. Plow was always set to 0 cmH2O. T-low was adjusted
 according to PCO2 value in blood gas measurement, by evaluating expiratory flow curve (gas
 flow wave form), and to get a release duration of 10-14.cycle-1. Tlow range was adjusted as
 0.4-1.2 seconds. When needed, Thigh was gradually increased to 12-15 seconds by increments of
 1-2 seconds. In case of hypoxemia, the problem was generally solved by increasing Phigh and
 FiO2, and as an additional strategy, Thigh was increased. In case of hypercapnia, sedation
 was lowered to allow spontaneous breaths. In order to increase the number of releases and
 thus, increase the minute-ventilation, Thigh was shortened and Phigh was increased 12,13.

 Weaning Process:

 Weaning was performed according to the European Respiratory Society Weaning Task Force
 recommendations in both groups 14. In APRV group, Phigh was reduced by 2-3 cmH2O and Thigh
 increased by 0.5-2.0 sec during weaning as the patient tolerated it. Tlow was kept constant
 at the same time. Before transfer to CPAP, Phigh was kept at approximately 14-16 cm H2O or
 lower, and Thigh was increased up to level of 10-12 sec. In P-SIMV+PS group, respiratory rate
 was reduced by 2 breaths.min-1, and PS level was reduced by decrements of 2-4 cmH2O. In both
 groups, spontaneous breathing trial was attempted for 30-60 minutes with T-tube when CPAP was
 5-10 cmH2O, and patients were extubated afterwards. For patients with tolerance, the same
 trial was repeated the next day. Total MV time was defined as the time passed from intubation
 to the last successful extubation. Patients who required tracheotomy during follow-up were
 recorded.

 Medical and Supportive Treatments:

 Preferred medications for those patients requiring sedation was midazolam infused at loading
 dose: 0.5 to 5 mg every 1 to 5 minutes (if needed), followed by 1 to 8 mg.hour-1 or 0.01 to
 0.1 mg.kg-1.hour-1 continuous infusion; titrate infusion rate to clinical effect; for
 analgesia, fentanyl infused at 1-2 mcg.kg-1.hr-1 i.v. The sedation goal was a Richmond
 Agitation Sedation Scale score of - 2 to 0 15. According to our clinic's sedation policy,
 Richmond Agitation Sedation Scale was assessed hourly by the nursing staff, and medication
 doses were titrated by the respiratory therapists according to target spontaneous respiration
 level. Evaluation of whether patients received sedation and the number of days which they
 received sedation were recorded. Sedation doses were not evaluated. None of the patients
 received neuromuscular blocker. Fluid management, antibiotic strategy, glucose control and
 enteral nutrition were also standardized between the two groups according to the ICU
 protocols.

 Statistical Analysis On the primary outcome of developing ARDS in the light of P/F ratio
 8[Clinically defined ALI/ARDS developed in the CMV group (mean [SE] PaO2/FIO2 [P/F] ratio,
 242.96 [S.E. 24.82]), and this was prevented with APRV (P/F ratio, 478.00 [S.E.41.38]; P <
 .05 vs CMV)], power analysis using the Gpower computer program11 indicated that a total
 sample of 58 people would be needed to detect large effects (d: 0.888) with 90% power using a
 t test between means with 2-tailed alpha at .05.

 All data were analyzed using IBM SPSS V23 (Chicago, USA). The Shapiro Wilk test was used to
 determine whether the data were normally distributed. Comparisons of data that were not
 normally distributed were made with the Kruskal Wallis test and the Mann Whitney U test.
 Categorical data were analyzed with the Pearson chi-square test. The groups were compared
 with regard to laboratory parameters measured on days 1, 2, 3, and 7. Non-normally
 distributed data were presented as median (min-max), while normally distributed data were
 presented as mean ± standard deviation. Categorical data were expressed as frequency and
 percentage. Values of p < .05 were considered significant.

 Study Endpoint The primary endpoint of the study was to determine whether APRV mode was
 protective against ARDS compared to the conventional mode in patients with high risk of ARDS
 as determined by LIPS score. The secondary endpoint was to determine whether this mode
 provided any improvement in oxygenation, airway pressures, sedation and inotrope
 requirements, mechanical ventilation time and length of ICU/hospital stay.
Inclusion Criteria:

 -  The study included patients who required invasive mechanical ventilation but was not
 initially diagnosed with ARDS 9, had a LIPS (Lung Injury Prediction Score) of > 7, and
 have been staying in the ICU for more than 24 hours.

 Exclusion Criteria:

 -  pregnancy

 -  intracranial hypertension (suspected or confirmed by measurement with external
 ventricular drainage catheter)

 -  severe chronic obstructive pulmonary disease or type II respiratory failure

 -  confirmed bronchopleural fistula

 -  documented barotrauma

 -  history of pneumonectomy