Повторный анализ исследования EPVent-2: какие дополнительные данные можно выделить

Статья

Автор: Caroline Brown

Дата: 02.03.2022

Чтобы повысить процент выживаемости среди пациентов с острым респираторным дистресс-синдромом, важно ограничить степень механического повреждения легких при инвазивной вентиляции (1).

Повторный анализ исследования EPVent-2: какие дополнительные данные можно выделить

Основные идеи

С помощью регулировки PEEP на основе пищеводного давления для достижения положительного транспульмонального давления можно точнее выполнять титрование для каждого пациента и снизить риск возникновения ателектравмы, ограничивая при этом чрезмерное расширение легких.
В ходе исследования EPVent-2 сравнивался результат титрования PEEP с помощью пищеводного баллона и результат использования стратегии эмпирически высокого PEEP-FiO2. Существенной разницы в показателях смертности или количестве дней без искусственной вентиляции легких обнаружено не было.
При последующем анализе полученных данных рассматривался вопрос, может ли лечебный эффект регулировки PEEP на основе значения «Pes» зависеть от наличия полиорганной недостаточности на момент включения в исследование.
В результате анализа была установлена тесная связь между степенью тяжести полиорганной недостаточности на момент включения в исследование и лечебным эффектом (на основании показателя смертности за 60 дней).

Pазные подходы

Подходы включают в себя использование меньших дыхательных объемов и ограниченного рабочего давления (Amato MB, Barbas CS, Medeiros DM, et al. Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome. N Engl J Med. 1998;338(6):347-354. doi:10.1056/NEJM1998020533806022, Acute Respiratory Distress Syndrome Network, Brower RG, Matthay MA, et al. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med. 2000;342(18):1301-1308. doi:10.1056/NEJM2000050434218013), преимущества которых были четко продемонстрированы, и титрование положительного давления в конце выдоха (PEEP). При этом такая стратегия PEEP должна уравновешивать преимущества рекрутмента легких и риски их чрезмерного расширения (Madahar P, Talmor D, Beitler JR. Transpulmonary Pressure-guided Ventilation to Attenuate Atelectrauma and Hyperinflation in Acute Lung Injury. Am J Respir Crit Care Med. 2021;203(8):934-937. doi:10.1164/rccm.202011-4116ED4). В этом случае доказательства менее очевидны. Исследования с использованием таблиц PEEP-FiO2 на основе оксигенации (Brower RG, Lanken PN, MacIntyre N, et al. Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome. N Engl J Med. 2004;351(4):327-336. doi:10.1056/NEJMoa0321935) или стратегии рекрутмента (Mercat A, Richard JC, Vielle B, et al. Positive end-expiratory pressure setting in adults with acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA. 2008;299(6):646-655. doi:10.1001/jama.299.6.6466) не продемонстрировали значительного влияния лечения на смертность, что позволяет предположить индивидуальный ответ на стратегию PEEP.

Результаты исследования EPVent-2

Используя в качестве ориентира пищеводное давление (оценку плеврального давления, Pes), можно осуществлять более точное титрование PEEP для каждого отдельного пациента, чтобы снизить риск возникновения ателектравмы, ограничивая при этом чрезмерное расширение легких. Это позволяет разделить механику легких и грудной клетки, определить предрасположенность легких к рекрутменту и оценить общую нагрузку на легкие (Chiumello D, Carlesso E, Cadringher P, et al. Lung stress and strain during mechanical ventilation for acute respiratory distress syndrome. Am J Respir Crit Care Med. 2008;178(4):346-355. doi:10.1164/rccm.200710-1589OC7, Beitler JR, Majumdar R, Hubmayr RD, et al. Volume Delivered During Recruitment Maneuver Predicts Lung Stress in Acute Respiratory Distress Syndrome. Crit Care Med. 2016;44(1):91-99. doi:10.1097/CCM.00000000000013558, Loring SH, O'Donnell CR, Behazin N, et al. Esophageal pressures in acute lung injury: do they represent artifact or useful information about transpulmonary pressure, chest wall mechanics, and lung stress?. J Appl Physiol (1985). 2010;108(3):515-522. doi:10.1152/japplphysiol.00835.20099, Talmor D, Sarge T, O'Donnell CR, et al. Esophageal and transpulmonary pressures in acute respiratory failure. Crit Care Med. 2006;34(5):1389-1394. doi:10.1097/01.CCM.0000215515.49001.A210). В исследовании EPVent-2 рассматривался вопрос о том, превосходит ли титрование PEEP с помощью пищеводного баллона стратегию с эмпирически высоким PEEP-FiO2 с точки зрения исходов у пациентов с острым респираторным дистресс-синдромом средней и тяжелой степени. Исследователи не обнаружили существенной разницы в показателях смертности или количестве дней без искусственной вентиляции легких между группой с PEEP, определяемым на основе значения «Pes», и группой с эмпирически высоким PEEP-FiO2 (Beitler JR, Sarge T, Banner-Goodspeed VM, et al. Effect of Titrating Positive End-Expiratory Pressure (PEEP) With an Esophageal Pressure-Guided Strategy vs an Empirical High PEEP-Fio2 Strategy on Death and Days Free From Mechanical Ventilation Among Patients With Acute Respiratory Distress Syndrome: A Randomized Clinical Trial. JAMA. 2019;321(9):846-857. doi:10.1001/jama.2019.055511).

Зачем проводился повторный анализ данных

В ходе недавнего повторного анализа данных (Sarge T, Baedorf-Kassis E, Banner-Goodspeed V, et al. Effect of Esophageal Pressure-guided Positive End-Expiratory Pressure on Survival from Acute Respiratory Distress Syndrome: A Risk-based and Mechanistic Reanalysis of the EPVent-2 Trial. Am J Respir Crit Care Med. 2021;204(10):1153-1163. doi:10.1164/rccm.202009-3539OC12) авторы оценили влияние полиорганной недостаточности и механики легких на эффект лечения. Они предположили, что, во-первых, лечебный эффект регулировки PEEP на основе значения «Pes» может зависеть от степени тяжести полиорганной недостаточности на момент включения в исследование, а, во-вторых, PEEP, титрованный до транспульмонального давления в конце выдоха (PL; PL = давление в дыхательных путях - плевральное давление) около 0 смH2O, повысит вероятность выживания.

Были проанализированы данные всех 200 пациентов, которые принимали участие в исследовании EPVent-2. Риск смерти из-за полиорганной недостаточности и хронических заболеваний на момент включения в исследование был оценен количественно по шкале оценки острых и хронических функциональных изменений II (APACHE-II). Средняя величина составила 27,5; значения ниже нее классифицировались как низкие показатели APACHE-II, а значения выше – как высокие показатели APACHE-II. Показатели APACHE-II были равномерно распределены между двумя группами (с PEEP, определяемым на основе значения «Pes», и эмпирически высоким PEEP: 27,0 ± 7,7 и 27,7 ± 7,4; P = 0,35). Средний исходный риск смерти на 60 день составлял 36,6% (межквартильный интервал: 29 - 43,0%) в группе с PEEP, определяемым на основе значения «Pes», и 37,6% (31,9 - 44,3%) в группе с эмпирически высоким PEEP (P = 0,34).

Роль полиорганной недостаточности на момент включения в исследование

В результате первичного анализа смертности за 60 дней было обнаружено тесную связь между эффектом регулировки PEEP на основе значения «Pes» и степенью тяжести заболевания на момент включения в исследование. Среди пациентов с низким показателем APACHE-II смертность за 60 дней составляла 20% в группе с PEEP, определяемым на основе значения «Pes», и 39,6% в группе с эмпирически высоким PEEP. В то же время среди пациентов с высокими показателями APACHE-II эффект был противоположным. Смертность за 60 дней среди пациентов с тяжелой степенью полиорганной недостаточности на момент включения в исследование была выше в группе с PEEP, определяемым на основе значения «Pes», чем в группе с эмпирически высоким PEEP. Эта связь со смертностью сохранялась во всех проведенных анализах, независимо от того, какой метод моделирования использовался, и даже когда показатель APACHE-II был заменен динамической оценкой органной недостаточности (SOFA).

вторы предлагают два возможных объяснения этих результатов. Во-первых, индивидуальное титрование PEEP, скорее всего, принесет пользу пациентам с острым респираторным дистресс-синдромом тяжелой степени, которые в первую очередь подвержены риску смерти из-за повреждения легких, а не из-за полиорганной недостаточности. У пациентов с тяжелой полиорганной недостаточностью больший риск развития гемодинамической нестабильности из-за чрезмерного раздувания легких может перевесить пользу защиты легких. Во-вторых, транспульмональное давление в конце вдоха было значительно выше в течение двух из первых трех дней в подгруппе пациентов с высокими показателями APACHE-II, которым PEEP определялось на основе значения «Pes». Поскольку более высокое транспульмональное давление в конце вдоха свидетельствует о гиперинфляции, это может объяснить худшие результаты у таких пациентов.

Касательно вторичных результатов, а именно количества дней без искусственной вентиляции легких и шока, связь была похожей. Лечебный эффект регулировки PEEP на основе значения «Pes» зависел от общей тяжести болезни на момент включения в исследование. У пациентов с низкими показателями APACHE-II при регулировке PEEP на основе значения «Pes» наблюдалось большее количество дней без искусственной вентиляции легких и шока, чем при использовании эмпирически высокого PEEP. Однако, в отличие от первичного результата, эта связь не подтвердилась при проведении ретроспективного анализа чувствительности.

Транспульмональное давление в конце выдоха и выживаемость

Вторым важным результатом этого исследования стала связь между выживаемостью и близостью транспульмонального давления в конце выдоха к 0 смH2O. Среди всех пациентов, независимо от группы и показателя APACHE-II, смертность была наименьшей при титровании PEEP до транспульмонального давления в конце выдоха, близкого к 0 смH2O. Вместо линейной связи между транспульмональным давлением в конце выдоха и смертностью авторы обнаружили, что значения между +2 и -2 смН2О ассоциируются с большей выживаемостью, в то время как значения вне этого диапазона в любом направлении, как было показано отдельно, ассоциируются с меньшей выживаемостью. Эта связь оставалась статистически значимой даже при учете транспульмонального давления в конце вдоха. Значения в пределах этого защитного диапазона также ассоциировались с большим количеством дней без искусственной вентиляции легких и шока.

Также интерес представляет более узкий диапазон значений транспульмонального давления в конце выдоха в группе с PEEP, определяемым на основе значения «Pes», в течение первых 4 дней, что может свидетельствовать о более точном титровании PEEP до транспульмонального давления. Кроме того, транспульмональное давление в конце выдоха было ближе к 0 смH2O в группе с PEEP, определяемым на основе значения «Pes», несмотря на то, что это не было конкретной целью данной стратегии.

Что дальше?

Эти результаты (хотя они получены в результате повторного анализа, не указанного в оригинальном протоколе исследования)<span class="msoDel"><span style="color:red">  свидетельствуют о необходимости дальнейшего изучения в проспективных исследованиях для оценки титрования PEEP до транспульмонального давления в конце выдоха ближе к 0 смH2O, принимая во внимание разнородность полиорганной недостаточности на момент включения в исследование.

Они также напоминают нам о важности учета гемодинамического состояния при выборе PEEP и указывают на то, что PEEP необходимо устанавливать таким образом, чтобы достичь транспульмонального давления в конце выдоха около 0 смH2O. Поэтому следует с осторожностью использовать высокое PEEP у пациентов с тяжелым шоком, особенно если выбранное PEEP приводит к тому, что транспульмональное давление в конце выдоха значительно превышает 0 смH2O.

Аппараты ИВЛ HAMILTON-G5/S1 (Not available in all marketsA) и HAMILTON-C6 имеют дополнительный порт для подключения линии давления пищеводного катетера*. Врач может вывести на экран кривую абсолютных значений пищеводного и транспульмонального давления.

Полная цитата ниже: (Slutsky AS, Ranieri VM. Ventilator-induced lung injury [published correction appears in N Engl J Med. 2014 Apr 24;370(17):1668-9]. N Engl J Med. 2013;369(22):2126-2136. doi:10.1056/NEJMra12087071)

Сноски

A. В некоторых странах могут быть доступны не все модели аппаратов ИВЛ

Список литературы

1. Slutsky AS, Ranieri VM. Ventilator-induced lung injury [published correction appears in N Engl J Med. 2014 Apr 24;370(17):1668-9]. N Engl J Med. 2013;369(22):2126-2136. doi:10.1056/NEJMra1208707
2. Amato MB, Barbas CS, Medeiros DM, et al. Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome. N Engl J Med. 1998;338(6):347-354. doi:10.1056/NEJM199802053380602
3. Acute Respiratory Distress Syndrome Network, Brower RG, Matthay MA, et al. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med. 2000;342(18):1301-1308. doi:10.1056/NEJM200005043421801
4. Madahar P, Talmor D, Beitler JR. Transpulmonary Pressure-guided Ventilation to Attenuate Atelectrauma and Hyperinflation in Acute Lung Injury. Am J Respir Crit Care Med. 2021;203(8):934-937. doi:10.1164/rccm.202011-4116ED
5. Brower RG, Lanken PN, MacIntyre N, et al. Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome. N Engl J Med. 2004;351(4):327-336. doi:10.1056/NEJMoa032193
6. Mercat A, Richard JC, Vielle B, et al. Positive end-expiratory pressure setting in adults with acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA. 2008;299(6):646-655. doi:10.1001/jama.299.6.646
7. Chiumello D, Carlesso E, Cadringher P, et al. Lung stress and strain during mechanical ventilation for acute respiratory distress syndrome. Am J Respir Crit Care Med. 2008;178(4):346-355. doi:10.1164/rccm.200710-1589OC
8. Beitler JR, Majumdar R, Hubmayr RD, et al. Volume Delivered During Recruitment Maneuver Predicts Lung Stress in Acute Respiratory Distress Syndrome. Crit Care Med. 2016;44(1):91-99. doi:10.1097/CCM.0000000000001355
9. Loring SH, O'Donnell CR, Behazin N, et al. Esophageal pressures in acute lung injury: do they represent artifact or useful information about transpulmonary pressure, chest wall mechanics, and lung stress?. J Appl Physiol (1985). 2010;108(3):515-522. doi:10.1152/japplphysiol.00835.2009
10. Talmor D, Sarge T, O'Donnell CR, et al. Esophageal and transpulmonary pressures in acute respiratory failure. Crit Care Med. 2006;34(5):1389-1394. doi:10.1097/01.CCM.0000215515.49001.A2
11. Beitler JR, Sarge T, Banner-Goodspeed VM, et al. Effect of Titrating Positive End-Expiratory Pressure (PEEP) With an Esophageal Pressure-Guided Strategy vs an Empirical High PEEP-Fio2 Strategy on Death and Days Free From Mechanical Ventilation Among Patients With Acute Respiratory Distress Syndrome: A Randomized Clinical Trial. JAMA. 2019;321(9):846-857. doi:10.1001/jama.2019.0555
12. Sarge T, Baedorf-Kassis E, Banner-Goodspeed V, et al. Effect of Esophageal Pressure-guided Positive End-Expiratory Pressure on Survival from Acute Respiratory Distress Syndrome: A Risk-based and Mechanistic Reanalysis of the EPVent-2 Trial. Am J Respir Crit Care Med. 2021;204(10):1153-1163. doi:10.1164/rccm.202009-3539OC

Ventilator-induced lung injury.

Slutsky AS, Ranieri VM. Ventilator-induced lung injury [published correction appears in N Engl J Med. 2014 Apr 24;370(17):1668-9]. N Engl J Med. 2013;369(22):2126-2136. doi:10.1056/NEJMra1208707

Link to article

Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome.

Amato MB, Barbas CS, Medeiros DM, et al. Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome. N Engl J Med. 1998;338(6):347-354. doi:10.1056/NEJM199802053380602

Link to article

BACKGROUND

In patients with the acute respiratory distress syndrome, massive alveolar collapse and cyclic lung reopening and overdistention during mechanical ventilation may perpetuate alveolar injury. We determined whether a ventilatory strategy designed to minimize such lung injuries could reduce not only pulmonary complications but also mortality at 28 days in patients with the acute respiratory distress syndrome.

METHODS

We randomly assigned 53 patients with early acute respiratory distress syndrome (including 28 described previously), all of whom were receiving identical hemodynamic and general support, to conventional or protective mechanical ventilation. Conventional ventilation was based on the strategy of maintaining the lowest positive end-expiratory pressure (PEEP) for acceptable oxygenation, with a tidal volume of 12 ml per kilogram of body weight and normal arterial carbon dioxide levels (35 to 38 mm Hg). Protective ventilation involved end-expiratory pressures above the lower inflection point on the static pressure-volume curve, a tidal volume of less than 6 ml per kilogram, driving pressures of less than 20 cm of water above the PEEP value, permissive hypercapnia, and preferential use of pressure-limited ventilatory modes.

RESULTS

After 28 days, 11 of 29 patients (38 percent) in the protective-ventilation group had died, as compared with 17 of 24 (71 percent) in the conventional-ventilation group (P<0.001). The rates of weaning from mechanical ventilation were 66 percent in the protective-ventilation group and 29 percent in the conventional-ventilation group (P=0.005): the rates of clinical barotrauma were 7 percent and 42 percent, respectively (P=0.02), despite the use of higher PEEP and mean airway pressures in the protective-ventilation group. The difference in survival to hospital discharge was not significant; 13 of 29 patients (45 percent) in the protective-ventilation group died in the hospital, as compared with 17 of 24 in the conventional-ventilation group (71 percent, P=0.37).

CONCLUSIONS

As compared with conventional ventilation, the protective strategy was associated with improved survival at 28 days, a higher rate of weaning from mechanical ventilation, and a lower rate of barotrauma in patients with the acute respiratory distress syndrome. Protective ventilation was not associated with a higher rate of survival to hospital discharge.

Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome.

Acute Respiratory Distress Syndrome Network, Brower RG, Matthay MA, et al. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med. 2000;342(18):1301-1308. doi:10.1056/NEJM200005043421801

Link to article

BACKGROUND

Traditional approaches to mechanical ventilation use tidal volumes of 10 to 15 ml per kilogram of body weight and may cause stretch-induced lung injury in patients with acute lung injury and the acute respiratory distress syndrome. We therefore conducted a trial to determine whether ventilation with lower tidal volumes would improve the clinical outcomes in these patients.

METHODS

Patients with acute lung injury and the acute respiratory distress syndrome were enrolled in a multicenter, randomized trial. The trial compared traditional ventilation treatment, which involved an initial tidal volume of 12 ml per kilogram of predicted body weight and an airway pressure measured after a 0.5-second pause at the end of inspiration (plateau pressure) of 50 cm of water or less, with ventilation with a lower tidal volume, which involved an initial tidal volume of 6 ml per kilogram of predicted body weight and a plateau pressure of 30 cm of water or less. The primary outcomes were death before a patient was discharged home and was breathing without assistance and the number of days without ventilator use from day 1 to day 28.

RESULTS

The trial was stopped after the enrollment of 861 patients because mortality was lower in the group treated with lower tidal volumes than in the group treated with traditional tidal volumes (31.0 percent vs. 39.8 percent, P=0.007), and the number of days without ventilator use during the first 28 days after randomization was greater in this group (mean [+/-SD], 12+/-11 vs. 10+/-11; P=0.007). The mean tidal volumes on days 1 to 3 were 6.2+/-0.8 and 11.8+/-0.8 ml per kilogram of predicted body weight (P<0.001), respectively, and the mean plateau pressures were 25+/-6 and 33+/-8 cm of water (P<0.001), respectively.

CONCLUSIONS

In patients with acute lung injury and the acute respiratory distress syndrome, mechanical ventilation with a lower tidal volume than is traditionally used results in decreased mortality and increases the number of days without ventilator use.

Transpulmonary Pressure-guided Ventilation to Attenuate Atelectrauma and Hyperinflation in Acute Lung Injury.

Madahar P, Talmor D, Beitler JR. Transpulmonary Pressure-guided Ventilation to Attenuate Atelectrauma and Hyperinflation in Acute Lung Injury. Am J Respir Crit Care Med. 2021;203(8):934-937. doi:10.1164/rccm.202011-4116ED

Link to article

Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome.

Brower RG, Lanken PN, MacIntyre N, et al. Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome. N Engl J Med. 2004;351(4):327-336. doi:10.1056/NEJMoa032193

Link to article

BACKGROUND

Most patients requiring mechanical ventilation for acute lung injury and the acute respiratory distress syndrome (ARDS) receive positive end-expiratory pressure (PEEP) of 5 to 12 cm of water. Higher PEEP levels may improve oxygenation and reduce ventilator-induced lung injury but may also cause circulatory depression and lung injury from overdistention. We conducted this trial to compare the effects of higher and lower PEEP levels on clinical outcomes in these patients.

METHODS

We randomly assigned 549 patients with acute lung injury and ARDS to receive mechanical ventilation with either lower or higher PEEP levels, which were set according to different tables of predetermined combinations of PEEP and fraction of inspired oxygen.

RESULTS

Mean (+/-SD) PEEP values on days 1 through 4 were 8.3+/-3.2 cm of water in the lower-PEEP group and 13.2+/-3.5 cm of water in the higher-PEEP group (P<0.001). The rates of death before hospital discharge were 24.9 percent and 27.5 percent, respectively (P=0.48; 95 percent confidence interval for the difference between groups, -10.0 to 4.7 percent). From day 1 to day 28, breathing was unassisted for a mean of 14.5+/-10.4 days in the lower-PEEP group and 13.8+/-10.6 days in the higher-PEEP group (P=0.50).

CONCLUSIONS

These results suggest that in patients with acute lung injury and ARDS who receive mechanical ventilation with a tidal-volume goal of 6 ml per kilogram of predicted body weight and an end-inspiratory plateau-pressure limit of 30 cm of water, clinical outcomes are similar whether lower or higher PEEP levels are used.

Positive end-expiratory pressure setting in adults with acute lung injury and acute respiratory distress syndrome: a randomized controlled trial.

Mercat A, Richard JC, Vielle B, et al. Positive end-expiratory pressure setting in adults with acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA. 2008;299(6):646-655. doi:10.1001/jama.299.6.646

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CONTEXT

The need for lung protection is universally accepted, but the optimal level of positive end-expiratory pressure (PEEP) in patients with acute lung injury (ALI) or acute respiratory distress syndrome remains debated.

OBJECTIVE

To compare the effect on outcome of a strategy for setting PEEP aimed at increasing alveolar recruitment while limiting hyperinflation to one aimed at minimizing alveolar distension in patients with ALI.

DESIGN, SETTING, AND PATIENTS

A multicenter randomized controlled trial of 767 adults (mean [SD] age, 59.9 [15.4] years) with ALI conducted in 37 intensive care units in France from September 2002 to December 2005.

INTERVENTION

Tidal volume was set at 6 mL/kg of predicted body weight in both strategies. Patients were randomly assigned to a moderate PEEP strategy (5-9 cm H(2)O) (minimal distension strategy; n = 382) or to a level of PEEP set to reach a plateau pressure of 28 to 30 cm H(2)O (increased recruitment strategy; n = 385).

MAIN OUTCOME MEASURES

The primary end point was mortality at 28 days. Secondary end points were hospital mortality at 60 days, ventilator-free days, and organ failure-free days at 28 days.

RESULTS

The 28-day mortality rate in the minimal distension group was 31.2% (n = 119) vs 27.8% (n = 107) in the increased recruitment group (relative risk, 1.12 [95% confidence interval, 0.90-1.40]; P = .31). The hospital mortality rate in the minimal distension group was 39.0% (n = 149) vs 35.4% (n = 136) in the increased recruitment group (relative risk, 1.10 [95% confidence interval, 0.92-1.32]; P = .30). The increased recruitment group compared with the minimal distension group had a higher median number of ventilator-free days (7 [interquartile range {IQR}, 0-19] vs 3 [IQR, 0-17]; P = .04) and organ failure-free days (6 [IQR, 0-18] vs 2 [IQR, 0-16]; P = .04). This strategy also was associated with higher compliance values, better oxygenation, less use of adjunctive therapies, and larger fluid requirements.

CONCLUSIONS

A strategy for setting PEEP aimed at increasing alveolar recruitment while limiting hyperinflation did not significantly reduce mortality. However, it did improve lung function and reduced the duration of mechanical ventilation and the duration of organ failure.

TRIAL REGISTRATION

clinicaltrials.gov Identifier: NCT00188058.

Lung stress and strain during mechanical ventilation for acute respiratory distress syndrome.

Chiumello D, Carlesso E, Cadringher P, et al. Lung stress and strain during mechanical ventilation for acute respiratory distress syndrome. Am J Respir Crit Care Med. 2008;178(4):346-355. doi:10.1164/rccm.200710-1589OC

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RATIONALE

Lung injury caused by a ventilator results from nonphysiologic lung stress (transpulmonary pressure) and strain (inflated volume to functional residual capacity ratio).

OBJECTIVES

To determine whether plateau pressure and tidal volume are adequate surrogates for stress and strain, and to quantify the stress to strain relationship in patients and control subjects.

METHODS

Nineteen postsurgical healthy patients (group 1), 11 patients with medical diseases (group 2), 26 patients with acute lung injury (group 3), and 24 patients with acute respiratory distress syndrome (group 4) underwent a positive end-expiratory pressure (PEEP) trial (5 and 15 cm H2O) with 6, 8, 10, and 12 ml/kg tidal volume.

MEASUREMENTS AND MAIN RESULTS

Plateau airway pressure, lung and chest wall elastances, and lung stress and strain significantly increased from groups 1 to 4 and with increasing PEEP and tidal volume. Within each group, a given applied airway pressure produced largely variable stress due to the variability of the lung elastance to respiratory system elastance ratio (range, 0.33-0.95). Analogously, for the same applied tidal volume, the strain variability within subgroups was remarkable, due to the functional residual capacity variability. Therefore, low or high tidal volume, such as 6 and 12 ml/kg, respectively, could produce similar stress and strain in a remarkable fraction of patients in each subgroup. In contrast, the stress to strain ratio-that is, specific lung elastance-was similar throughout the subgroups (13.4 +/- 3.4, 12.6 +/- 3.0, 14.4 +/- 3.6, and 13.5 +/- 4.1 cm H2O for groups 1 through 4, respectively; P = 0.58) and did not change with PEEP and tidal volume.

CONCLUSIONS

Plateau pressure and tidal volume are inadequate surrogates for lung stress and strain. Clinical trial registered with www.clinicaltrials.gov (NCT 00143468).

Volume Delivered During Recruitment Maneuver Predicts Lung Stress in Acute Respiratory Distress Syndrome.

Beitler JR, Majumdar R, Hubmayr RD, et al. Volume Delivered During Recruitment Maneuver Predicts Lung Stress in Acute Respiratory Distress Syndrome. Crit Care Med. 2016;44(1):91-99. doi:10.1097/CCM.0000000000001355

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OBJECTIVE

Global lung stress varies considerably with low tidal volume ventilation for acute respiratory distress syndrome. High stress despite low tidal volumes may worsen lung injury and increase risk of death. No widely available parameter exists to assess global lung stress. We aimed to determine whether the volume delivered during a recruitment maneuver (V(RM)) is inversely associated with lung stress and mortality in acute respiratory distress syndrome.

DESIGN

Substudy of an acute respiratory distress syndrome clinical trial on esophageal pressure-guided positive end-expiratory pressure titration.

SETTING

U.S. academic medical center.

PATIENTS

Forty-two patients with acute respiratory distress syndrome in whom airflow, airway pressure, and esophageal pressure were recorded during the recruitment maneuver.

INTERVENTIONS

A single recruitment maneuver was performed before initiating protocol-directed ventilator management. Recruitment maneuvers consisted of a 30-second breath hold at 40 cm H2O airway pressure under heavy sedation or paralysis. V(RM) was calculated by integrating the flow-time waveform during the maneuver. End-inspiratory stress was defined as the transpulmonary (airway minus esophageal) pressure during end-inspiratory pause of a tidal breath and tidal stress as the transpulmonary pressure difference between end-inspiratory and end-expiratory pauses.

MEASUREMENTS AND MAIN RESULTS

V(RM) ranged between 7.4 and 34.7 mL/kg predicted body weight. Lower V(RM) predicted high end-inspiratory and tidal lung stress (end-inspiratory: β = -0.449; 95% CI, -0.664 to -0.234; p < 0.001; tidal: β = -0.267; 95% CI, -0.423 to -0.111; p = 0.001). After adjusting for PaO2/FIO2 and either driving pressure, tidal volume, or plateau pressure and positive end-expiratory pressure, V(RM) remained independently associated with both end-inspiratory and tidal stress. In unadjusted analysis, low V(RM) predicted increased risk of death (odds ratio, 0.85; 95% CI, 0.72-1.00; p = 0.026). V(RM) remained significantly associated with mortality after adjusting for study arm (odds ratio, 0.84; 95% CI, 0.71-1.00; p = 0.022).

CONCLUSIONS

Low V(RM) independently predicts high lung stress and may predict risk of death in patients with acute respiratory distress syndrome.

Esophageal pressures in acute lung injury: do they represent artifact or useful information about transpulmonary pressure, chest wall mechanics, and lung stress?

Loring SH, O'Donnell CR, Behazin N, et al. Esophageal pressures in acute lung injury: do they represent artifact or useful information about transpulmonary pressure, chest wall mechanics, and lung stress?. J Appl Physiol (1985). 2010;108(3):515-522. doi:10.1152/japplphysiol.00835.2009

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Acute lung injury can be worsened by inappropriate mechanical ventilation, and numerous experimental studies suggest that ventilator-induced lung injury is increased by excessive lung inflation at end inspiration or inadequate lung inflation at end expiration. Lung inflation depends not only on airway pressures from the ventilator but, also, pleural pressure within the chest wall. Although esophageal pressure (Pes) measurements are often used to estimate pleural pressures in healthy subjects and patients, they are widely mistrusted and rarely used in critical illness. To assess the credibility of Pes as an estimate of pleural pressure in critically ill patients, we compared Pes measurements in 48 patients with acute lung injury with simultaneously measured gastric and bladder pressures (Pga and P(blad)). End-expiratory Pes, Pga, and P(blad) were high and varied widely among patients, averaging 18.6 +/- 4.7, 18.4 +/- 5.6, and 19.3 +/- 7.8 cmH(2)O, respectively (mean +/- SD). End-expiratory Pes was correlated with Pga (P = 0.0004) and P(blad) (P = 0.0104) and unrelated to chest wall compliance. Pes-Pga differences were consistent with expected gravitational pressure gradients and transdiaphragmatic pressures. Transpulmonary pressure (airway pressure - Pes) was -2.8 +/- 4.9 cmH(2)O at end exhalation and 8.3 +/- 6.2 cmH(2)O at end inflation, values consistent with effects of mediastinal weight, gravitational gradients in pleural pressure, and airway closure at end exhalation. Lung parenchymal stress measured directly as end-inspiratory transpulmonary pressure was much less than stress inferred from the plateau airway pressures and lung and chest wall compliances. We suggest that Pes can be used to estimate transpulmonary pressures that are consistent with known physiology and can provide meaningful information, otherwise unavailable, in critically ill patients.

Esophageal and transpulmonary pressures in acute respiratory failure.

Talmor D, Sarge T, O'Donnell CR, et al. Esophageal and transpulmonary pressures in acute respiratory failure. Crit Care Med. 2006;34(5):1389-1394. doi:10.1097/01.CCM.0000215515.49001.A2

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OBJECTIVE

Pressure inflating the lung during mechanical ventilation is the difference between pressure applied at the airway opening (Pao) and pleural pressure (Ppl). Depending on the chest wall's contribution to respiratory mechanics, a given positive end-expiratory and/or end-inspiratory plateau pressure may be appropriate for one patient but inadequate or potentially injurious for another. Thus, failure to account for chest wall mechanics may affect results in clinical trials of mechanical ventilation strategies in acute respiratory distress syndrome. By measuring esophageal pressure (Pes), we sought to characterize influence of the chest wall on Ppl and transpulmonary pressure (PL) in patients with acute respiratory failure.

DESIGN

Prospective observational study.

SETTING

Medical and surgical intensive care units at Beth Israel Deaconess Medical Center.

PATIENTS

Seventy patients with acute respiratory failure.

INTERVENTIONS

Placement of esophageal balloon-catheters.

MEASUREMENTS AND MAIN RESULTS

Airway, esophageal, and gastric pressures recorded at end-exhalation and end-inflation Pes averaged 17.5 +/- 5.7 cm H2O at end-expiration and 21.2 +/- 7.7 cm H2O at end-inflation and were not significantly correlated with body mass index or chest wall elastance. Estimated PL was 1.5 +/- 6.3 cm H2O at end-expiration, 21.4 +/- 9.3 cm H2O at end-inflation, and 18.4 +/- 10.2 cm H2O (n = 40) during an end-inspiratory hold (plateau). Although PL at end-expiration was significantly correlated with positive end-expiratory pressure (p < .0001), only 24% of the variance in PL was explained by Pao (R = .243), and 52% was due to variation in Pes.

CONCLUSIONS

In patients in acute respiratory failure, elevated esophageal pressures suggest that chest wall mechanical properties often contribute substantially and unpredictably to total respiratory impedance, and therefore Pao may not adequately predict PL or lung distention. Systematic use of esophageal manometry has the potential to improve ventilator management in acute respiratory failure by providing more direct assessment of lung distending pressure.

Effect of Titrating Positive End-Expiratory Pressure (PEEP) With an Esophageal Pressure-Guided Strategy vs an Empirical High PEEP-Fio2 Strategy on Death and Days Free From Mechanical Ventilation Among Patients With Acute Respiratory Distress Syndrome: A Randomized Clinical Trial.

Beitler JR, Sarge T, Banner-Goodspeed VM, et al. Effect of Titrating Positive End-Expiratory Pressure (PEEP) With an Esophageal Pressure-Guided Strategy vs an Empirical High PEEP-Fio2 Strategy on Death and Days Free From Mechanical Ventilation Among Patients With Acute Respiratory Distress Syndrome: A Randomized Clinical Trial. JAMA. 2019;321(9):846-857. doi:10.1001/jama.2019.0555

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Importance

Adjusting positive end-expiratory pressure (PEEP) to offset pleural pressure might attenuate lung injury and improve patient outcomes in acute respiratory distress syndrome (ARDS).

Objective

To determine whether PEEP titration guided by esophageal pressure (PES), an estimate of pleural pressure, was more effective than empirical high PEEP-fraction of inspired oxygen (Fio2) in moderate to severe ARDS.

Design, Setting, and Participants

Phase 2 randomized clinical trial conducted at 14 hospitals in North America. Two hundred mechanically ventilated patients aged 16 years and older with moderate to severe ARDS (Pao2:Fio2 ≤200 mm Hg) were enrolled between October 31, 2012, and September 14, 2017; long-term follow-up was completed July 30, 2018.

Interventions

Participants were randomized to PES-guided PEEP (n = 102) or empirical high PEEP-Fio2 (n = 98). All participants received low tidal volumes.

Main Outcomes and Measures

The primary outcome was a ranked composite score incorporating death and days free from mechanical ventilation among survivors through day 28. Prespecified secondary outcomes included 28-day mortality, days free from mechanical ventilation among survivors, and need for rescue therapy.

Results

Two hundred patients were enrolled (mean [SD] age, 56 [16] years; 46% female) and completed 28-day follow-up. The primary composite end point was not significantly different between treatment groups (probability of more favorable outcome with PES-guided PEEP: 49.6% [95% CI, 41.7% to 57.5%]; P = .92). At 28 days, 33 of 102 patients (32.4%) assigned to PES-guided PEEP and 30 of 98 patients (30.6%) assigned to empirical PEEP-Fio2 died (risk difference, 1.7% [95% CI, -11.1% to 14.6%]; P = .88). Days free from mechanical ventilation among survivors was not significantly different (median [interquartile range]: 22 [15-24] vs 21 [16.5-24] days; median difference, 0 [95% CI, -1 to 2] days; P = .85). Patients assigned to PES-guided PEEP were significantly less likely to receive rescue therapy (4/102 [3.9%] vs 12/98 [12.2%]; risk difference, -8.3% [95% CI, -15.8% to -0.8%]; P = .04). None of the 7 other prespecified secondary clinical end points were significantly different. Adverse events included gross barotrauma, which occurred in 6 patients with PES-guided PEEP and 5 patients with empirical PEEP-Fio2.

Conclusions and Relevance

Among patients with moderate to severe ARDS, PES-guided PEEP, compared with empirical high PEEP-Fio2, resulted in no significant difference in death and days free from mechanical ventilation. These findings do not support PES-guided PEEP titration in ARDS.

Trial Registration

ClinicalTrials.gov Identifier NCT01681225.

Effect of Esophageal Pressure-guided Positive End-Expiratory Pressure on Survival from Acute Respiratory Distress Syndrome: A Risk-based and Mechanistic Reanalysis of the EPVent-2 Trial.

Sarge T, Baedorf-Kassis E, Banner-Goodspeed V, et al. Effect of Esophageal Pressure-guided Positive End-Expiratory Pressure on Survival from Acute Respiratory Distress Syndrome: A Risk-based and Mechanistic Reanalysis of the EPVent-2 Trial. Am J Respir Crit Care Med. 2021;204(10):1153-1163. doi:10.1164/rccm.202009-3539OC

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Rationale: In acute respiratory distress syndrome (ARDS), the effect of positive end-expiratory pressure (PEEP) may depend on the extent to which multiorgan dysfunction contributes to risk of death, and the precision with which PEEP is titrated to attenuate atelectrauma without exacerbating overdistension. Objectives: To evaluate whether multiorgan dysfunction and lung mechanics modified treatment effect in the EPVent-2 (Esophageal Pressure-guided Ventilation 2) trial, a multicenter trial of esophageal pressure (Pes)-guided PEEP versus empirical high PEEP in moderate to severe ARDS. Methods: This post hoc reanalysis of the EPVent-2 trial evaluated for heterogeneity of treatment effect on mortality by baseline multiorgan dysfunction, determined via Acute Physiology and Chronic Health Evaluation II (APACHE-II). It also evaluated whether PEEP titrated to end-expiratory transpulmonary pressure near 0 cm H2O was associated with survival. Measurements and Main Results: All 200 trial participants were included. Treatment effect on 60-day mortality differed by multiorgan dysfunction severity (P = 0.03 for interaction). Pes-guided PEEP was associated with lower mortality among patients with APACHE-II less than the median value (hazard ratio, 0.43; 95% confidence interval, 0.20-0.92) and may have had the opposite effect in patients with higher APACHE-II (hazard ratio, 1.69; 95% confidence interval, 0.93-3.05). Independent of treatment group or multiorgan dysfunction severity, mortality was lowest when PEEP titration achieved end-expiratory transpulmonary pressure near 0 cm H2O. Conclusions: The effect on survival of Pes-guided PEEP, compared with empirical high PEEP, differed by multiorgan dysfunction severity. Independent of multiorgan dysfunction, PEEP titrated to end-expiratory transpulmonary pressure closer to 0 cm H2O was associated with greater survival than more positive or negative values. These findings warrant prospective testing in a future trial.