急性呼吸窘迫综合征完整通气支持适应性支持通气:一个试点,随机对照试验

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Adaptive support ventilation (ASV) is a closed-loop ventilation mode for which the ven-tilator adjusts inspiratory pressure to achieve a tidal volume that minimizes the work of breathing.
适应性支持通气(ASV)是调节吸气压力达到一定潮气量,呼吸做功最小化的闭环通气模式

Sixty-one patients undergoing elective fast-track cardiac valvular surgery were randomly assigned to receive and be weaned using ASV or be ventilated and weaned as directed by duty physicians (control group).
61例经历选择性快速心脏瓣膜手术患者， 随机分配两组： ASV通气模式组和实验对照组。
ASV reduced the duration of mechanical ventilation in the intensive care unit by more than 2 h, from a median of 342 min in the control group to 205 min in the ASV group. ASV also reduced the number of manual ventilator setting changes and the number of ventilator alarms.
重症监护室ASV通气模式平均减少患者支持通气2 h以上，ASV组205分钟，对照组342分钟。
ASV通气模式同时减少人工调节呼吸机参数设置次数和呼吸机警报的次数。

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Background and objective
Low tidal volume ventilation has been shown to improve survival in acute respiratory distress syndrome (ARDS). Adaptive support ventilation (ASV), a closed-loop ventilatory mode, can minimize the work of breathing, and thus potentially improve the outcomes in ARDS. The aim of this pilot, randomized clinical trial was to compare the outcomes of ASV versus volume-cycled ventilation (VCV) in ARDS.
低潮气量呼吸支持通气可以改善急性呼吸窘迫综合征(ARDS)的生存。适应性支持通气(ASV),一个闭环通气模式,可以减少呼吸做功,从而可能改善ARDS的预后。本试验的目：随机临床实验比较应用ASV和volume-cycled(VCV)通气模式ARDS病人预后。

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Methods
Patients with ARDS were randomly allocated to either ASV or VCV. The primary outcomes were duration of mechanical ventilation, new-onset organ dysfunction and hospital length of stay. The secondary outcomes were ease of use of the ventilator mode (assessed using the visual analogue scale (VAS)), number of daily arterial blood gas analyses, daily requirements of sedative and neuromuscular blockers, and mortality.
ARDS患者被随机分两组ASV组或VCV组。记录呼吸机支持通气时间,初发器官功能障碍和住院时间。其次记录易于使用的呼吸机模式(评估使用视觉模拟量表),每天的动脉血气分析、镇静神经肌肉阻滞剂,每日所需的蛋白质和死亡率。

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Results
Forty-eight patients (28 males, 20 females) with ARDS were randomized to receive either ASV (n = 23) or VCV (n = 25) during the study period. The baseline characteristics were almost similar in the two groups. The duration of mechanical ventilation, delta sequential organ failure assessment scores, intensive care unit and hospital stay were comparable in the two groups. The mortality (VCV-36% vs ASV-34.7%), ease of use of mechanical ventilation, daily midazolam and vecuronium doses, and the number of arterial blood gas analyses performed were also similar in the two groups.
48例ARDS患者(男性28例,女性20例)，研究期间随机分配接受ASV(n = 23)或VCV(n = 25)。两组基线特征几乎相似。呼吸支持通气时间,delta 器官顺序衰竭评估分数，比较两组重症监护室天数和住院天数，死亡率( VCV - 36%， ASV- 34.7%), 易于使用的呼吸支持模式,每日咪达唑仑剂量和维库剂量,动脉血气分析的结果，两组表现类似。

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Conclusions
There was no significant difference in the outcomes of patients with ARDS ventilated with either VCV or ASV in this study.
结果;这项研究中VCV或ASV呼吸支持模式对ARDS患者预后没有显著性差异。

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Abbreviations:
ARDS
acute respiratory distress syndrome急性呼吸窘迫综合征
ASV
adaptive support ventilation适应性支持通气
fR
respiratory rate呼吸频率
ICU
intensive care unit重症监护室
MV
minute ventilation没分通气量
PEEP
positive end expiratory pressure呼吸末正压通气
Pinsp
inspiratory pressure on ASV  ASV呼吸压力
Pplat
plateau pressure平台压
VAS
visual analogue scale视觉模拟评分
VCV
volume-cycled ventilation
Vt
tidal volume潮气量

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Introduction
Acute respiratory distress syndrome (ARDS) is a disease characterized by acute inflammation and increased permeability of pulmonary parenchyma caused by varying aetiologies, in the absence of left atrial hypertension.[1] Since its initial description,[2] ARDS has been associated with significant mortality.[3, 4] There is no specific pharmacological treatment of ARDS. As ventilator-associated lung injury is an important cause of poor clinical outcomes in ARDS, ventilatory strategies are aimed at reducing the incidence and severity of ventilator-associated lung injury. Newer ventilatory modes utilize algorithms that perform breath-to-breath calculation of respiratory mechanics, thereby ensuring adequate minute ventilation with least possible airway pressures,[5] thereby decreasing the risk of ventilator-associated lung injury.

Adaptive support ventilation (ASV) is a closed-loop mode introduced in 1994 by Laubscher and coworkers that automatically switches from pressure control ventilation to pressure-control synchronized intermittent mandatory ventilation or pressure support ventilation, depending on the patient's status.[6, 7] ASV works as per the Otis equation, thereby minimizing the work of breathing.[8] Unlike pressure control ventilation (or pressure-control synchronized intermittent mandatory ventilation) or pressure support ventilation, ASV guarantees preset minute ventilation with an optimal breathing pattern, independent of patient activity or effort. With ASV, the clinician sets the desired minute ventilation, and the ventilator algorithm calculates the best respiratory rate (fR) and tidal volume (Vt) combination for the spontaneous and mandatory breaths according to the patient's respiratory mechanics.[9] The ventilator calculates the minute ventilation based on the patient's ideal body weight and the estimated dead space volume (2.2 mL/kg). This represents 100% minute volume, and the clinician can set minute volumes greater than 100% in those with increased requirements as in ARDS or less than 100% as in weaning. The use of ASV could lead to potential improvement in patient–ventilator synchrony and pattern of breathing, thereby decreasing ventilator-associated lung injury, as it is now debated that the asynchrony can theoretically amplify ventilator-associated lung injury.[10] ASV can deliver complete or partial ventilatory support during the initial stages or the weaning phase of ventilatory support.

Theoretically, ASV could improve the outcomes of patients with ARDS. However, studies evaluating ASV in ARDS have examined only the physiological parameters.[11-14] No study has reported the clinical outcomes (such as ventilator days, hospital length of stay, mortality), or has utilized ASV for complete ventilatory support in ARDS. We have previously reported our experience in managing patients with ARDS using both invasive and non-invasive mechanical ventilation.[15-17] We hypothesized that ASV would be as effective as conventional low Vt ventilation in ventilating patients with ARDS. The objectives of this study were to assess the duration of mechanical ventilation and hospital length of stay in patients ventilated with ASV versus conventional ventilatory protocol. In this pilot, randomized controlled trial, we compare the outcomes of ASV versus volume-cycled ventilation (VCV) in managing ARDS.
Introduction
急性呼吸窘迫综合征(ARDS)：其典型特征是肺急性炎症和各种原因造成肺实质通透增加,左心房压力不高一类疾病总称。首次描述以来ARDS一直与死亡率显著相关。没有具体的药物治疗ARDS。呼吸机相关肺损伤是ARDS较坏临床结果的重要原因,通气策略旨在减少与机械通气相关肺损伤的发生率和严重程度。新的通气模式利用breath-to-breath呼吸力学的计算,从而确保足够的每分通气量尽可能低气道压力,从而减少机械通气相关肺损伤的风险。适应性支持通气(ASV)是一个闭环模式，由Laubscher 和同事于1994年根据病人的状态推出的自动切换压力控制通气、压力控制同步间歇强制通气或压力支持通气的通气模式。ASV工作原理按照奥蒂斯方程,从而减少呼吸做功。与压力控制通气(或压力控制同步间歇强制通风)或压力支持通气,ASV保证预定每分通气量与最优的呼吸模式，,独立于病人的活动或工作。ASV,根据病人的呼吸力学临床医生集所需的每分通气量和呼吸机算法结合自然和强制计算最佳的呼吸速率(fR)和潮气量(Vt)。根据病人的理想体重和估计死腔体积(2.2毫升/公斤)呼吸机计算每分通气量。这是100%的分钟通气量,临床医生根据ARDS患者需求可以设置分钟通气大于100%或不到100%。ASV的使用可能会致潜在改善同步的呼吸模式,从而使机械通气相关肺损伤减少,因为它是现在讨论非同步可以理论上放大与机械通气相关肺损伤。初始阶段或者通气支持期ASV可以提供完全或部分通气支持。理论上,ASV可以改善ARDS患者的预后。然而,研究评估ASV  ARDS患者只检查生理参数。没有临床结果研究报道(如呼吸支持天数,住院时间,死亡率),或利用ASV ARDS的完整的通气支持。我们之前报道的管理经验ARDS患者使用侵入性和非侵入性的机械通风。我们推测,ARDS患者ASV会尽可能有效的可能低通气量。本研究的目的是评估机械通气的持续时间长度与ASV呼吸支持和传统通气模式。随机对照试验,我们比较ARDS ASV和volume-cycled(VCV)管理的结果。

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Methods
This was a prospective randomized clinical trial conducted between 1 July 2009 and 30 June 2011 in the respiratory intensive care unit of our institute. The respiratory intensive care unit is an eight-bedded, closed intensive care unit (ICU) with five on-call consultants, five pulmonary fellows posted during a 24-h shift and a nurse-to-patient ratio of 1:2.5. The study was approved by the ethics review committee (PGIMER, Chandigarh), and informed consent was obtained from all patients (or next of kin). The trial is registered with http://www.clinicaltrials.gov (NCT01165528).

这是一项前瞻性随机临床试验，2009年7月1日至2011年6月30日我们研究所的呼吸重症监护室。呼吸重症监护病房有8张床位,封闭的重症监护室(ICU)和五个随叫随到顾问,五个肺科同事24小时期间轮转并且护士与病人比率2.5 :1。这项研究通过伦理审查委员会(PGIMER, Chandigarh)，并获得所有患者(或最亲的亲戚)知情同意。The trial is registered with http://www.clinicaltrials.gov (NCT01165528).

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Patient selection
Patients with ARDS requiring invasive mechanical ventilation were eligible for inclusion in the study if they met all the following:[1] (i) acute onset dyspnoea (<7 days); (ii) PaO2/FIO2 <200 mm Hg; (iii) bilateral opacities on chest radiograph; and (iv) no clinical evidence of left atrial hypertension. Patients were excluded from the study if they demonstrated any of the following: failure to provide informed consent, age <12 years, pregnancy, chronic lung disease and contraindications to permissive hypercapnea. Patients meeting the inclusion criteria were randomized to either VCV or ASV group (Fig. 1). The randomization sequence was computer-generated, and the assignments were placed in sealed opaque envelopes. The assignment to each arm was made on admission by the attending physician. Blinding of treatment was not possible.
病人的选择
如果ARDS患者需要侵入性机械通气符合所有以下:[1](i)急性发作呼吸困难(< 7天);(2)PaO2 /供给< 200毫米汞柱;(3)双边胸部有阴影;及(iv)没有左心房高血压的临床证据有资格列入研究对象。排除下列:未能提供知情同意、年龄< 12年、怀孕、慢性肺部疾病和禁忌症。符合入选标准的患者被随机分为VCV或ASV组(图1)。计算机生成的随机序列,序列号放置于密封的不透明信封中。入院患者由主治医生分配到每个组。不可能双盲治疗。

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Study procedure
Initially, all patients were passively ventilated (completely sedated and paralyzed) with low Vt strategy (6 mL/kg predicted body weight) with FIO2/positive end expiratory pressure (PEEP) as per the ARDSnet protocol to determine the appropriate minute ventilation (MV).[18, 19] In patients randomized to VCV, the same strategy was continued. The aim was to achieve a SpO2 of 88–92%, with the lowest FIO2 at a plateau pressure (Pplat) of ≤30–35 cm H2O and pH >7.3. The Vt could be reduced to 4 mL/kg predicted body weight and fR increased to 35/min to achieve these goals if necessary.
In the ASV group, the minute ventilation attained with initial VCV was used to guide the initial setting of percentage MV (%MV). FIO2/PEEP was set according to ARDSnet protocol to maintain SpO2 of 88–92% at minimum possible FIO2. The peak pressure alarm was set at 45 cm H2O to avoid Pplat from exceeding 35 cm H2O. Subsequent manipulation of %MV was guided by interpretation of the following parameters: Pinsp, spontaneous respiratory frequency while on ASV (fspont) and target respiratory frequency (ftarget) calculated by the ASV algorithm. If the fspont was greater than ftarget by 10 breaths and/or associated was hypoxaemia (PaO2<55 mm Hg or SpO2 <88%) or hypercapnic acidosis (pH <7.25), then the %MV was escalated by 20%. If the fspont was similar to ftarget without any hypercapnea or hypoxaemia, then the %MV was de-escalated by 10%. The pressurization slope (percentage of the inspiratory time taken to reach the peak pressure) was maintained at 25% for all subjects. All patients were ventilated with Galileo Gold ventilators (Hamilton Medical, Bonaduz, Switzerland).
研究过程
最初,所有患者呼吸支持(完全镇静和瘫痪)低潮气量(6毫升/公斤体重)预测与FIO2/PEEP按照ARDS协议来确定适当的每分通气量(MV)。患者随机分为VCV,继续相同的策略。目的是达到SpO288 - 92%,最低的供给平台压力(Pplat)≤30 - 35厘米水和pH > 7.3。如果必要Vt可以减少4毫升/公斤体重和预测呼吸频率增加到35 次/分钟。


ASV组,每分通气量达到最初VCV是用于指导MV的初始设置百分比(% MV)。FIO2/PEEP是根据ARDS协议维持SpO2 88 - 92%的最低可能的供给。峰值压力报警被设定在45厘米水柱,避免Pplat超过35厘米水柱。后续操作% MV是由以下参数调整:Pinsp、ASV自发呼吸频率(fspont)和ASV计算目标(频率。如果fspont大于ftarget 10呼吸相关和/或低血氧症(PaO2 < 55毫米汞柱或SpO2 < 88%)或高碳酸血症酸中毒(pH值< 7.25),然后增大20% % MV。如果fspont类似ftarget没有任何呼吸过度或低血氧症,然后逐步降级10% MV。增压坡(比例的吸气时间达到峰值压力)是所有科目保持在25%。所有患者通气 Galileo Gold ventilators (Hamilton Medical, Bonaduz, Switzerland).

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Sedation protocol
A standard protocol was used in all patients. During the first 48 h, all patients received intravenous midazolam infusion titrated to a Richmond Agitation-Sedation Scale (RASS) score of 0 to −2. Pain was assessed using behavioural pain scale and managed with intravenous fentanyl/morphine boluses. Patients received vecuronium only if the fR was >35/min or if there was significant patient–ventilator dyssynchrony (based on the physician's assessment of ventilator tracings, as well as clinical assessment). After 48 h, patients were administered intravenous midazolam boluses of 2–4 mg only if fR exceeded 35/min or in the presence of significant patient–ventilator dyssynchrony. However, the patient was started on continuous infusion of midazolam if there was requirement of frequent midazolam boluses (≥2/h).
镇静方案
所有患者使用标准方案。第一个48 h,所有患者接受静脉注射咪达唑仑， Richmond Agitation-Sedation Scale (RASS)评分为0−2。行为疼痛量表评估疼痛，使用静脉芬太尼/吗啡药丸。患者fR > 35 /分钟或如果有重大过程不同步只应用维库(根据医生的呼吸机追踪评估,以及临床评估)。48小时后,只有病人fR超过35 /分钟呼吸不同步静脉注射咪达唑仑2 - 4毫克。然而,如果病人有要求频繁的咪达唑仑(≥2 /小时)，开始持续注入咪达唑仑。

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Weaning protocol
Patients in the VCV arm were shifted to pressure support (PS) ventilation once the PEEP and FIO2 requirements decreased to 8 cm H2O and 0.4, respectively (Fig. 1), according to our previously published protocol.[20] The PS used was the Pplat recorded during the VCV mode (PSmax). PS was gradually decreased by 2 cm H2O every 6 h (or earlier) until PS of 7 cm H2O. Subsequently, the patient was given a spontaneous breathing trial with T-piece (off ventilator) for 1 h. If the patient tolerated the spontaneous breathing trial,[20] he or she was extubated. In the ASV arm, weaning was initiated by monitoring the trends for Pinsp, total fR and spontaneous/control fR. Once deemed fit, weaning was achieved by sequential decrease in %MV every 2 h (or earlier). Spontaneous breathing trial was considered once %MV was ≤70% and Pinsp was ≤8 cm of H2O. Patients were extubated if they were able to tolerate the spontaneous breathing trial for 60 min (Fig. 1).



脱机方案
VCV组的病人转移到压力支持(PS)通气，一旦 PEEP and FIO2供分别降低到8厘米水柱,和0.4 ,(图1),根据我们以前公布的方案。VCV Pplat记录使用的PS模式(PSmax)。PS逐渐下降了2厘米水每6小时(或更早),直到PS 7厘米水柱。随后,病人自发呼吸试验T-piece (off ventilator) 1 h。如果病人忍受自主呼吸试验,他或她拔管。ASV,脱机是Pinsp发起监控趋势,总fR和自发的/控制fR。一旦认为适合,脱机是通过连续下降% MV每2小时(或更早)。自主呼吸试验被认为是一旦% MV≤70%,Pinsp≤8厘米水柱。如果他们能够忍受自主呼吸试验60分钟，患者拔管(图1)。

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End-points and definitions
We collected the following data: clinical history and physical examination, age, gender, and duration of illness. The severity of the underlying illness was scored using the acute physiology and chronic health evaluation II and the sequential organ failure assessment scores.[21, 22] The ventilatory parameters, including Vt, FIO2 and PEEP settings, peak and Pplat, %MV, and peak inspiratory pressure on ASV (Pinsp), were monitored continuously and documented every 12 h or after any change by the attending physician. The ease of ventilator mode was broadly assessed using the visual analogue scale (VAS). The VAS is a measurement instrument for subjective characteristics or attitudes that cannot be directly measured. The VAS is measured on a scale from 0 to 100 mm, with 0 being extremely easy to use and 100 being extremely complicated. The physicians specified their level of agreement by indicating a position along a continuous line between two end-points. The VAS was measured during every shift of the ICU physician, and then an average was calculated. Sedative and neuromuscular blockers were administered using the above-mentioned protocol, and the cumulative daily dose was calculated. Arterial blood gas analysis was performed when indicated.
The primary outcome measures were the duration of mechanical ventilation, new-onset organ dysfunction (assessed by delta sequential organ failure assessment score),[16] and hospital and ICU length of stay. The secondary outcome measures were mortality, ease of use of the ventilator mode assessed by VAS, number of arterial blood gas analysis per day, and daily requirements of sedative and neuromuscular blocking agents.
我们收集以下数据:病史和体格检查,年龄、性别、疾病和持续时间。潜在疾病的严重程度得分使用急性生理和慢性健康评估 II 和顺序器官衰竭评估分数。 通气参数,Vt, FIO2 and PEEP settings, peak and Pplat, %MV, and peak inspiratory pressure on ASV (Pinsp),,连续监测并记录每12小时或任何改变后的主治医生,便于通风模式是广泛使用视觉模拟量表评估(血管),脉管是主观特征或态度的测量仪不能直接测量,测量血管范围从0到100毫米,0是非常容易使用,100极其复杂。他们的协议指定的医生指示的位置在两个端点之间的连线。血管测量在ICU医生的每一个变化,然后计算平均。镇静和神经肌肉阻滞剂使用上述协议管理,和累积剂量计算。执行动脉血气分析。


主要结果措施是机械通气的时间,始器官功能障碍(assessed by delta sequential organ failure assessment score),医院天数和ICU住院时间。其次结果死亡率、易于使用的呼吸机模式评估血管,每天动脉血气分析,每日所需的镇静剂和神经肌肉阻断剂。

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Sample size
Assuming a mortality rate of 31% in the VCV arm and decline in mortality by 5% in the ASV arm, we would require 1751 patients in each arm (confidence level (1-α) 95%, power level (1-β) 90%) to detect these differences. Assuming a mean (standard deviation) duration of mechanical ventilation of 10 (7) days in the VCV arm and decrease by 2 days in the ASV arm, we would require 194 patients in each group. As it was not feasible to perform such a large study, a pilot study was performed.
样本的大小
假设VCV组死亡率31%和ASV组死亡率下降5% ,我们将需要1751名患者(置信度(1-α)95%,(1-β)90%)来检测这些差异。假设意味着(标准偏差)机械通气时间VCV 10(7)天,ASV减少2天,我们需要每组194例。这是不可行的执行这样的大型研究,初步试点研究。