Incidence of dyssynchronous spontaneous Breathing Effort, breath-stacking and reverse triggering in early ARDS. - The BEARDS project -

Incidence of dyssynchronous spontaneous Breathing Effort, breath-stacking and reverse triggering in early ARDS - The BEARDS project - Scientific committee: Tai Pham Martin Dres Irene Telias Tommaso Mauri Jordi Mancebo Giacomo Bellani Ewan Goligher Lluis Blanch Laurent Brochard Investigator contact: Dr Laurent Brochard Medical and Surgical Intensive Care Unit Saint Michael s Hospital Toronto, ON, M5G 1X5 Canada E-mail: BrochardL@smh.ca 1

Objectives and specific aims of the project The acute respiratory distress syndrome (ARDS) is a leading concern in the intensive care unit (ICU) since it is associated with high morbidity and mortality. There are no specific treatments but a lung protective ventilation strategy aiming at providing oxygenation and minimizing lung injury is systematically used (1). The major causes of death in patients with ARDS are multiorgan failure secondary to sepsis, hemodynamic compromise, severe hypoxemia and possibly ventilator-induced lung injury (VILI) (2). VILI is recognized to be the constellation of pulmonary consequences of mechanical ventilation that could potentially lead to increase in systemic inflammatory response and contribute to multiorgan failure (3). A key factor for VILI is attributed to regional lung overdistention induced by ventilation support. Recent data suggest that ventilation in general, i.e. not only the ventilator, may contribute to lung injury and that patients breathing spontaneously with high respiratory drive may develop a form of patient self-inflicted lung injury (P-SILI), quite similar to VILI (4). At the early phase of ARDS, neuromuscular blocking agents (NBMA) have shown their efficacy to improve adjusted 90-day survival rate and time off the ventilator in selected individuals (5). The results were unexpected given the benefits potentially offered by maintaining some degree of spontaneous breathing activity. By paralyzing respiratory muscles, NMBA may indirectly minimize the occurrence of mechanisms leading to ventilation-induced lung injury, either VILI or P-SILI. A period of paralysis early in the course of ARDS may thus facilitate the delivery of lung-protective mechanical ventilation by avoiding patient ventilator interaction, thereby limiting the risk of dyssynchrony-related alveolar collapse and regional alveolar overdistention. On the other hand, the neuromuscular blocking agents put the respiratory muscles completely at rest and this could result in disuse atrophy and muscle weakness that may lead to difficult weaning and worst prognosis (6, 7). Experimental data suggest that spontaneous breathing in the context of acute lung injury can be either beneficial or detrimental depending on the severity of lung injury (8). There are different mechanisms which can explain the negative impact of spontaneous breathing. One may be the occurrence of breath stacking. Large spontaneous diaphragmatic contractions can also be triggered by the ventilator, in heavily sedated, non-paralyzed patients with ARDS (i.e., reverse triggering) (9). Spontaneous breathing effort may also cause regional injury by augmenting regional tidal volumes (10). Therefore, it is unclear what precisely explains the benefit of neuromuscular blocking agents in patients with ARDS but a better monitoring of non-paralyzed patients 2

experiencing spontaneous breathing during mechanical ventilation could help to prevent negative effects of spontaneous breathing based on the different mechanisms described. Moreover, the prevalence and potential harmful effects of reverse triggering have never been extensively investigated in this specific context. The use of NMBA is not universal and is usually transient and often partial. We think that an observation of patients with ARDS, even under deep sedation, with or without NMBA (transiently) is needed to understand the occurrence of inspiratory efforts and dyssynchrony (spontaneous or triggered by the mechanical ventilator), in the early phase of ARDS or at the transition to partial modes of ventilation. This will inform how to best manage these asynchronies regarding ventilation, sedation and paralysis, potentially resulting in better short- and long-term outcomes for these patients. In the present study, we aim at assessing the incidence, physiological and clinical consequences of spontaneous breathing effort, dyssynchrony and reverse triggering at the early phase of ARDS in continuously sedated patients during controlled ventilation and at the time of transition to partial ventilatory support. More specifically, the objectives will be: 1) To describe the incidence of spontaneous breathing efforts, reverse triggering (either inducing double cycles or associated with eccentric contractions during expiration), breath stacking and short cycles (with a potential for eccentric contractions of the respiratory muscles), as well as other asynchronies like wasted efforts. 2) To analyze the presence of main dyssynchronies (including reverse triggering) with its corresponding changes in transpulmonary pressure swings, plateau pressure and volume delivered by the ventilator in those breaths, and quantify the breathing efforts generated 3) To associate the incidence of dyssynchronies (including reverse triggering) during the early phase of ARDS with outcome (ventilator free days, intensive care unit (ICU) stay, mortality, pneumothorax as secondary outcome). 4) To understand the relationship between sedation levels and regimens and the different types of dyssynchronies. Relevance 3

ARDS is a life threatening disease that affects approximately 70 to 80 patients/100 000 habitants annually and is associated with a mortality estimated at over 40% (11, 12). ARDS is also an important and costly public health problem associated with long-term disabilities, exercise limitations and a reduced physical quality of life until 5 years after the diagnosis (13). The use of neuromuscular blocking agents has shown positive effect on survival for the most severe patients but the exact mechanisms of this benefit is unclear, and the risks of negative impact on respiratory muscle function and prolonged mechanical ventilation are high (5, 14). This study aims at trying to understand the possible mechanisms of the paradoxical benefit of neuromuscular blocking agents through decrease of dyssynchronies and at informing how a better monitoring and management could help. Indeed, the findings could provide robust data on the incidence/prevalence of different types of dyssynchronies and suggest changes in therapy from neuromuscular blocking agents and sedation. Background The speculative positive effect of NMBA at the early phase of ARDS could be associated with three different mechanisms, as suggested by recent observations in ARDS patients under mechanical ventilation and deep sedation. Akoumianaki and colleagues observed repetitive decrease in esophageal pressure occurring regularly near the end of each mechanical inspiration in heavily sedated patients (9). Inspiratory efforts were directly triggered by the mechanical insufflations. This was observed during both pressure or volume controlled ventilation. This new kind of neuro-mechanical coupling was previously reported as a phenomenon of respiratory entrainment to mechanical ventilation in animals, healthy humans or chronically ventilated patients, and preterm infants. In the ICU, it might result in eccentric contractions of respiratory muscles, i.e., potentially injurious to the muscles, in extra-breaths going unrecognized (inducing double cycling and breath stacking with the undesirable consequence of delivering a high tidal volume) and in unreliable inspiratory pressure measurements. Double cycling, short cycles and breath stacking have also been observed in ARDS having a high respiratory drive (15) and a recent report indicated that stacked breaths in ARDS deliver tidal volume close to 12 ml/kg (16). Distinguishing the two types of breath stacking is essential, since one might be related to an excess in sedation (Reverse triggering), whereas the other is usually treated by sedation and it usually needs 4

readjustment of ventilatory settings (17). Last, Yoshida et al. reported both in animals and patients spontaneously breathing on the ventilator the existence of pendelluft, which resulted in internal lung volume redistribution and regional hyperinflation without any increase in global tidal volume (10). The latter dyssynchrony can be suspected in case of high respiratory drive, which can be estimated by the occlusion pressure or P0.1 (18). The use of neuromuscular blocking agents at the early phase of ARDS might avoid all these abnormalities and could have participated to the benefits observed (9) but this solution can only be transient, has side effects and cannot be universal. For instance, ARDS patients improving their oxygenation are usually transferred to a partial ventilatory mode. The different dyssynchronies may thus reappear at the time of transition from controlled ventilation to partial assist ventilation. Last, recent data show that ARDS often exhibit breath stacking representing tidal volumes of at least 11 ml/kg PBW (19). Present state of knowledge The lung protective ventilation strategy is now proposed as standard care for patients presenting with ARDS by using low tidal volume of 6 ml kg 1 predicted body weight and limiting the inspiratory plateau pressure to <28 30 cmh2o. Implementation of the lung protective ventilation strategy in patients exhibiting high respiratory drive and work of breathing may often lead to development of patient ventilator dyssynchrony, such as double triggering, despite administration of sedative and analgesic agents. There is a need for either selecting the patients that would benefit from the positive effect of NMBA or, preferably, from a better adaptation of settings and of sedation to minimize dyssynchronies (17). Spontaneous breathing efforts and dyssynchronies have been observed in mechanically ventilated patients with ARDS, however there are no data regarding the incidence, physiological and clinical consequence of these phenomena. A specific computerized electronic system has been developed to detect all kinds of dyssynchronies, by Lluis Blanch and his research group, able to capture physiological data such as ventilator waveforms and other physiological signals (http://www.bettercare.es/). This will be used to automatically capture, store and analyze recordings in a homogeneous way. Project design, methodology and analysis 5

The present project is an observational multicenter physiological study that will be conduct in several ICU in different countries. St Michel s Hospital s in Toronto, Canada, will be the leading coordinating center. Population Mechanically ventilated patients under continuous sedation will be considered for enrolment in the first week of ARDS diagnosis Inclusion criteria: Moderate and severe ARDS according to the Berlin definition (20, 21) Continuous intravenous sedation Deep sedation: Richmond Agitation Sedation Scale (RASS) < or equal -2 Non inclusion criteria <18 years Patients with a significant bronchopleural fistula Central nervous system or neuromuscular disorders NMBA Patient may or may not receive NMBAs. Sample size calculation Based on the previous reports, we assume a prevalence of breathing effort ranging from 10% to 100% of the recording time. To associate occurrence of breathing effort and change in respiratory mechanics and with potential clinical outcome, we estimate that a convenient sample of 120 patients would be suitable. With 15 centers participating, that would be an average of 8 patients per center. Each centre should have a minimum of 5 patients with esophageal catheter or electrical activity recording. It is possible to enroll additional patients without esophageal pressure or electrical activity of the diaphragm (contraindication, impossible placement or reliable recording). These patients will be analyzed by BetterCare without respiratory muscle signal. Recruitment There are two ways to recruit patients, the healthcare team (physicians, nurses, respiratory therapists, pharmacists) will be asked to contact the research team every time a mechanically ventilated patient meets criteria for hypoxemic acute respiratory failure with a PaO2/FiO2 ratio less than 300 mmhg. Other criteria will be screened for the diagnosis of ARDS, moderate 6

or severe. The research team will confirm that the patient meets the inclusion criteria without any of the exclusion criteria. The research team will screen daily the patients in the ICU to recognize patients that meet criteria for moderate or severe ARDS. Once recognized, inclusion and exclusion criteria will be analyzed for eligibility. Measurements Physiological measurements Airway pressure, esophageal pressure, electrical activity of the diaphragm and flow 1) A flow sensor with a differential pressure transducer and an additional port for pressure measurement will be connected to the endotracheal tube proximal to the Y connector. This will allow the continuous recordings of flow and proximal airway pressure. 2) In centers used to perform esophageal pressure measurements, an esophageal catheter will be inserted, checked for accuracy with an occlusion test (22), and connected to a 3 ways stopcock and a pressure transducer. Some patients may already have an esophageal catheter inserted, otherwise it will be inserted for the study. 3) If available, in centers used to record or monitor the electrical activity of the diaphragm, instead of an esophageal catheter, the electrical activity of the diaphragm will be provided by a catheter dedicated to the monitoring of the electrical activity of the diaphragm, or EaDi, on a Servo-I or Servo-U ventilator (Maquet, Lund, Sweden). This catheter is formally designed to be used for a specific mode of ventilation called Neurally Adjusted Ventilatory Assist (NAVA) but here will be used for monitoring purposes only (NAVA catheter). Any ventilator can be used if an esophageal pressure is used. 4) In case the esophageal catheter cannot be placed or is contraindicated, it is still possible to enroll the patient and limit the recordings to airway pressure and flow (the BetterCare system will analyze those without esophageal pressure after validation of the criteria for detection). Each centre should have a minimum of 5 patients with esophageal catheter or electrical activity recording. Data collection At the beginning of the recordings, ventilatory settings will be collected: ventilator brand, mode of ventilation and settings including: FiO2, PEEP, set and real tidal volume (or pressure), set and real respiratory rate, maximum inspiratory flow, inspiratory time, inspiratory on 7

expiratory times ratio (I:E ratio), plateau pressure (defined as the inspiratory pressure at the end of inspiration), EAdi or esophageal pressure. At the same time, physiological variables will be collected as well: heart rate, arterial pressure, pulse oximetry, Glasgow coma scale and Richmond Agitation Sedation Scale. Any medications used at the day of the measurement and before will be collected especially neuromuscular blocking agents, sedatives (brands and doses), opiates and vasopressors including dose, duration of the treatment and date of last use. We will also collect clinical characteristics of the patients (SAPS and SOFA at ICU admission and at the day of the recording, main ARDS etiology, age, gender, weight, height, days of mechanical ventilation, patient s position supine vs prone-, kidney and liver function). Other comorbidities will be recorded, with special emphasis in the ones that could affect the incidence of the studied phenomenon, such as: COPD, lung transplant or any neuromuscular condition that could affect the respiratory drive or respiratory muscle function. The most recent arterial blood gases will be collected. Patient will be follow up to get the total duration of mechanical ventilation, ICU length of stay, day of the first weaning attempt, day of tracheotomy if any, status at ICU discharge (alive or death) and at hospital discharge and at day 60. Experimental procedure A period of a minimum of 1h (and up to 2h) of continuous measurement, during the day, at a time of the day when minimal external intervention is planned (major nursing procedures, line or tube insertion, move to radiology department or the operating theater) will be performed. Any change in the patient condition during the measurement will be written as notes in the acquisition software. The recordings are planned to be repeated three days over a seven day period, and stopped in case of extubation, death or the 8 th day after the first recording. Analysis Data will be recorded on the acquisition system of the unit, depending on local procedure and will be later transformed into.txt files (or ASCII files) indicating the sampling frequency (from 100 to 250 Hz), with one column per parameter and one row per sample. All files will be analyzed similarly by an automated system (BetterCare ) based on validated algorithms to detect spontaneous breathing and dyssynchrony (23). Files containing esophageal pressure traces and / or EaDi will be analyzed based on these signals. Other files will be analyzed based 8

on airway pressure and flow recordings. The algorithms will be validated with the files containing esophageal pressure or EaDi first. The patient s work of breathing and the pressure-time product of the esophagus (PTPes), being the integral of the esophageal pressure over time limited by the chest wall recoil pressure, will be analyzed using a commercially available software (FluxReview and FluxMed ). Paw, Flow, Pes and transpulmonary pressure will be used (17, 24). The PTPes will be used to quantify the inspiratory muscle activity even when no inspiratory volume is generated. Other parameters will be also calculated: driving pressure (being the difference between plateau pressure and PEEP in passive cycles and the difference between plateau pressure and the lowest esophageal pressure in a cycle with respiratory muscle activity). Changes in transpulmonary pressure will also be calculated. The primary outcome will be the prevalence of dyssynchronies, including reverse triggering, breath stacking, short cycles and the quantification of spontaneous breathing efforts associated with dyssynchronies. Driving pressure, transpulmonary swings, plateau pressure and presence of asynchronies will be compared in cycles with and without reverse triggering and spontaneous breathing efforts. Clinical outcomes will be correlated with the incidence of each main type of dyssynchronies. Statistical analysis Data will be analyzed using descriptive statistics and will be expressed as mean standard deviation, medians, and the Interquartile range. Prevalence of dyssynchrony (reverse triggering, double triggering, double cycling, breath stacking, short cycles and eccentric contractions) will be described by the calculation of an asynchrony index, defined as the number of asynchrony events divided by the total respiratory rate computed as the sum of the number of ventilator cycles (triggered or not) and of wasted efforts: asynchrony Index (expressed in percentage) = number of asynchrony events/total respiratory rate (ventilator cycles +wasted efforts or number of efforts counted on the esophageal pressure tracing or Eadi recording) x 100. Real total minute ventilation (given by the ventilator) will be also compared to the theoretical total minute ventilation (calculated by: set respiratory rate times set tidal volume) during the period of analysis. 9

The coefficient of variation (CV) of the tidal volume, plateau pressure and driving pressure will be computed and compared between respiratory cycles with and without asynchronies. The relation between dyssynchronies and outcome will be tested through multivariate logistic analysis taking into account age, cause of respiratory failure/ards, general and respiratory severity indexes into account. Ethics This study protocol will be submitted to each Hospital s Research Ethics Board for evaluation and approval before beginning the study. Informed consent will be obtained from a substitute decision-maker (SDM) prior to any study procedures and data recording. In the case the patient already has an esophageal catheter in place or a NAVA catheter in place, consent will still be asked for the recordings. 10

References 1. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med 2000; 342: 1301-1308. 2. Ricard JD, Dreyfuss D, Saumon G. Ventilator-induced lung injury. Eur Respir J Suppl 2003; 42: 2s-9s. 3. Slutsky AS, Tremblay LN. Multiple system organ failure. Is mechanical ventilation a contributing factor? Am J Respir Crit Care Med 1998; 157: 1721-1725. 4. Brochard L, Slutsky A, Pesenti A. MECHANICAL VENTILATION TO MINIMIZE PROGRESSION OF LUNG INJURY IN ACUTE RESPIRATORY FAILURE. Am J Respir Crit Care Med 2016; In press. 5. Papazian L, Forel JM, Gacouin A, Penot-Ragon C, Perrin G, Loundou A, Jaber S, Arnal JM, Perez D, Seghboyan JM, Constantin JM, Courant P, Lefrant JY, Guerin C, Prat G, Morange S, Roch A. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med 2010; 363: 1107-1116. 6. Goligher EC, Fan E, Herridge MS, Murray A, Vorona S, Brace D, Rittayamai N, Lanys A, Tomlinson G, Singh JM, Bolz SS, Rubenfeld GD, Kavanagh BP, Brochard LJ, Ferguson ND. Evolution of Diaphragm Thickness during Mechanical Ventilation. Impact of Inspiratory Effort. Am J Respir Crit Care Med 2015; 192: 1080-1088. 7. Dres M, Dube BP, Mayaux J, Delemazure J, Reuter D, Brochard L, Similowski T, Demoule A. Coexistence and Impact of Limb Muscle and Diaphragm Weakness at Time of Liberation From Mechanical Ventilation in Medical ICU Patients. Am J Respir Crit Care Med 2016. 8. Yoshida T, Uchiyama A, Matsuura N, Mashimo T, Fujino Y. Spontaneous breathing during lung-protective ventilation in an experimental acute lung injury model: high transpulmonary pressure associated with strong spontaneous breathing effort may worsen lung injury. Crit Care Med 2012; 40: 1578-1585. 9. Akoumianaki E, Lyazidi A, Rey N, Matamis D, Perez-Martinez N, Giraud R, Mancebo J, Brochard L, Marie Richard JC. Mechanical ventilation-induced reverse-triggered breaths: a frequently unrecognized form of neuromechanical coupling. Chest 2013; 143: 927-938. 10. Yoshida T, Torsani V, Gomes S, De Santis RR, Beraldo MA, Costa EL, Tucci MR, Zin WA, Kavanagh BP, Amato MB. Spontaneous effort causes occult pendelluft during mechanical ventilation. Am J Respir Crit Care Med 2013; 188: 1420-1427. 11. Rubenfeld GD, Caldwell E, Peabody E, Weaver J, Martin DP, Neff M, Stern EJ, Hudson LD. Incidence and outcomes of acute lung injury. N Engl J Med 2005; 353: 1685-1693. 12. Bellani G, Laffey JG, Pham T, Fan E, Brochard L, Esteban A, Gattinoni L, van Haren F, Larsson A, McAuley DF, Ranieri M, Rubenfeld G, Thompson BT, Wrigge H, Slutsky AS, Pesenti A. Epidemiology, Patterns of Care, and Mortality for Patients With Acute Respiratory Distress Syndrome in Intensive Care Units in 50 Countries. JAMA 2016; 315: 788-800. 13. Herridge MS, Tansey CM, Matte A, Tomlinson G, Diaz-Granados N, Cooper A, Guest CB, Mazer CD, Mehta S, Stewart TE, Kudlow P, Cook D, Slutsky AS, Cheung AM. Functional disability 5 years after acute respiratory distress syndrome. N Engl J Med 2011; 364: 1293-1304. 11

14. Slutsky AS. Neuromuscular blocking agents in ARDS. N Engl J Med 2010; 363: 1176-1180. 15. Kallet RH, Luce JM. Detection of patient-ventilator asynchrony during low tidal volume ventilation, using ventilator waveform graphics. Respir Care 2002; 47: 183-185. 16. Beitler JR, Majumdar R, Hubmayr RD, Malhotra A, Thompson BT, Owens RL, Loring SH, Talmor D. Volume Delivered During Recruitment Maneuver Predicts Lung Stress in Acute Respiratory Distress Syndrome. Crit Care Med 2016; 44: 91-99. 17. Chanques G, Kress JP, Pohlman A, Patel S, Poston J, Jaber S, Hall JB. Impact of ventilator adjustment and sedation-analgesia practices on severe asynchrony in patients ventilated in assist-control mode. Crit Care Med 2013; 41: 2177-2187. 18. Mancebo J, Albaladejo P, Touchard D, Bak E, Subirana M, Lemaire F, Harf A, Brochard L. Airway occlusion pressure to titrate positive end-expiratory pressure in patients with dynamic hyperinflation. Anesthesiology 2000; 93: 81-90. 19. Beitler JR, Sands SA, Loring SH, Owens RL, Malhotra A, Spragg RG, Matthay MA, Thompson BT, Talmor D. Quantifying unintended exposure to high tidal volumes from breath stacking dyssynchrony in ARDS: the BREATHE criteria. Intensive Care Med 2016; 42: 1427-1436. 20. Ferguson ND, Fan E, Camporota L, Antonelli M, Anzueto A, Beale R, Brochard L, Brower R, Esteban A, Gattinoni L, Rhodes A, Slutsky AS, Vincent JL, Rubenfeld GD, Thompson BT, Ranieri VM. The Berlin definition of ARDS: an expanded rationale, justification, and supplementary material. Intensive Care Med 2012; 38: 1573-1582. 21. Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, Fan E, Camporota L, Slutsky AS. Acute respiratory distress syndrome: the Berlin Definition. JAMA 2012; 307: 2526-2533. 22. Akoumianaki E, Maggiore SM, Valenza F, Bellani G, Jubran A, Loring SH, Pelosi P, Talmor D, Grasso S, Chiumello D, Guerin C, Patroniti N, Ranieri VM, Gattinoni L, Nava S, Terragni PP, Pesenti A, Tobin M, Mancebo J, Brochard L. The application of esophageal pressure measurement in patients with respiratory failure. Am J Respir Crit Care Med 2014; 189: 520-531. 23. Blanch L, Sales B, Montanya J, Lucangelo U, Garcia-Esquirol O, Villagra A, Chacon E, Estruga A, Borelli M, Burgueno MJ, Oliva JC, Fernandez R, Villar J, Kacmarek R, Murias G. Validation of the Better Care(R) system to detect ineffective efforts during expiration in mechanically ventilated patients: a pilot study. Intensive Care Med 2012; 38: 772-780. 24. Brochard L, Martin GS, Blanch L, Pelosi P, Belda FJ, Jubran A, Gattinoni L, Mancebo J, Ranieri VM, Richard JC, Gommers D, Vieillard-Baron A, Pesenti A, Jaber S, Stenqvist O, Vincent JL. Clinical review: Respiratory monitoring in the ICU - a consensus of 16. Crit Care 2012; 16: 219. 12