0
Original Research: Critical Care |

Mechanical Ventilation-Induced Reverse-Triggered BreathsReverse Triggering: A Frequently Unrecognized Form of Neuromechanical Coupling FREE TO VIEW

Evangelia Akoumianaki, MD; Aissam Lyazidi, PhD; Nathalie Rey, MD; Dimitrios Matamis, MD; Nelly Perez-Martinez, MD; Raphael Giraud, MD; Jordi Mancebo, MD; Laurent Brochard, MD; Jean-Christophe Marie Richard, MD, PhD
Author and Funding Information

From the Intensive Care Unit Division (Drs Akoumianaki, Lyazidi, Rey, Matamis, Perez-Martinez, Giraud, Brochard, Richard), Anesthesiology Pharmacology and Intensive Care Department, and the School of Medicine (Drs Lyazidi, Brochard, and Richard), University of Geneva, Geneva, Switzerland; and Hospital Sant Pau (Dr Mancebo), Servei de Medicina Intensiva, Barcelona, Spain.

Correspondence to: Jean-Christophe M. Richard, MD, PhD, Soins Intensifs, Hopitaux Universitaires de Genève, Rue Gabrielle-Perret-Gentil 4, 1211 Geneva 14, Switzerland; e-mail: jcm.richard@hcuge.ch


Funding/Support: The authors have reported to CHEST that no funding was received for this study.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2013;143(4):927-938. doi:10.1378/chest.12-1817
Text Size: A A A
Published online

Background:  Diaphragmatic muscle contractions triggered by ventilator insufflations constitute a form of patient-ventilator interaction referred to as “entrainment,” which is usually unrecognized in critically ill patients. Our objective was to review tracings, which also included muscular activity, obtained in sedated patients who were mechanically ventilated to describe the entrainment events and their characteristics. The term “reverse triggering” was adopted to describe the ventilator-triggered muscular efforts.

Methods:  Over a 3-month period, recordings containing flow, airway pressure, and esophageal pressure or electrical activity of the diaphragm were reviewed. Recordings were obtained from a series of consecutive heavily sedated patients ventilated with an assist-control mode of ventilation for ARDS. The duration of entrainment, the entrainment ratio, and the phase difference elapsing between the commencement of the ventilator and neural breaths were evaluated.

Results:  The tracings of eight consecutive patients with ARDS were reviewed; they all showed different forms of entrainment. Reverse triggering occurred over a portion varying from 12% to 100% of the total recording period. Seven patients had a 1:1 mechanical insufflation to diaphragmatic contractions ratio; this coexisted with a 1:2 ratio in one patient and 1:2 and 1:3 ratios in another. One patient exhibited only a 1:2 ratio. The frequency of reverse-triggered breaths had a mean coefficient of variability of < 5%, very close to the variability of mechanical breaths.

Conclusions:  To our knowledge, this is the first time that the presence of respiratory entrainment in sedated, critically ill adult patients who are mechanically ventilated has been documented. The “reverse-triggered” breaths illustrate a new form of neuromechanical coupling with potentially important clinical consequences.

Figures in this Article

In physics, the term “entrainment” refers to the alignment of the phase and period of a nonlinear oscillatory system to the phase and period of a periodic external input. In respiratory physiology, “respiratory entrainment” (also called “respiratory phase locking”) refers to the establishment of a fixed repetitive temporal relationship between the neural and mechanical respiratory cycles.1

Studies in animals and normal humans have shown that the respiratory rhythm can be entrained or phase locked to extrinsic periodic mechanical inflations imposed during controlled mechanical ventilation.2-8 The pathogenesis involves the activation of vagally mediated pulmonary reflexes, along with cortical and subcortical influences.5-7,9-11

The current study arose from an accidental observation: In a patient with a continuous esophageal pressure (Pes) recording, inspiratory efforts occurred near the end of each mechanical inspiration in a repetitive and consistent manner. Subsequently, we reviewed available recordings of patients with an esophageal or a diaphragmatic electrical activity (EAdi) catheter in place, searching for similar entrainment phenomena.

We adopted the term “reverse triggering” to describe these muscular efforts apparently triggered by the ventilator. To our knowledge, this case series represents the first description of respiratory entrainment in critically ill patients and introduces a new form of patient-ventilator interaction: “reverse triggering.” Because it has a large number of potential clinical consequences, a better recognition of this phenomenon and a better knowledge of the mechanism at play are worthy of attention.

This study was approved by the ethics committee of Geneva University Hospital (Comité départemental d’éthique NAC, NAC 12-032R). Because of the descriptive character of the study, informed consent from the patients was not required.

Subjects

The study was conducted at the adult medicosurgical ICU of the University Hospital of Geneva. Over a 3-month period (January 2012 to March 2012), available recordings of flow, airway pressure (Paw), and Pes or EAdi of consecutive patients admitted to the ICU and ventilated with an assist-control mode of ventilation were inspected visually. We detected whether the patients were, at some point during their recording time, entrained with the ventilator and, if so, the characteristics of this patient-ventilator relationship were identified. The patients’ demographic characteristics, causes of admission, arterial blood gas levels, and ventilator features were collected from a computerized ICU database. Furthermore, the level of sedation, as assessed by the Richmond Agitation-Sedation Scale (RASS), was recorded.12

Data Acquisition

Six patients had an esophageal balloon catheter placed for measurements of respiratory mechanics. Differential pressure transducers (Validyne MP 45; Validyne Engineering) and a pneumotachograph (Fleisch No. 2, Fleisch) connected to the respiratory circuit were used to record pressures (Paw, Pes) and flow, respectively. The signals were acquired with an analog-digital converter (MP 100; BIOPAC Systems, Inc) sampled at 200 Hz. In two patients with a dedicated catheter (EAdi catheter; MAQUET Holding GmbH & Co KG), EAdi, flow, and Paw were obtained by means of a dedicated software (NAVA tracker SV 1.3; MAQUET Holding GmbH & Co KG). All recordings were stored in a laptop computer and were analyzed using commercially available software (Acknowledge 3.7.3; BIOPAC Systems, Inc).

Definition of Terms and Data Analysis

Entrainment was defined as a pattern in which the inspiratory efforts of the patient occurred over a specific and repetitive phase of the ventilator cycle, therefore, with a minimal variability of their neural respiratory time (Ttotneu).7 To express the latter, the coefficient of variation (CV) of the ventilator cycle duration (Ttotmech) and the CV of the Ttotneu of entrained and nonentrained breaths were compared. In the case of entrainment periods at some point during the recordings, the following descriptive parameters were evaluated on a breath-by-breath basis: (1) the duration of the entrainment, (2) the entrainment pattern or ratio, and (3) the phase difference (dP) (Fig 1). The entrainment ratio corresponded to the number of neural breaths within each ventilator breath. Hence, in a 1:1 entrainment ratio, one neural respiratory cycle was associated with one machine cycle; in a 1:2 ratio, one neural effort occurred every other machine cycle, and so forth. Of note, we reasoned that to be classified as respiratory entrainment, the 1:1 ratio had to be apparent in more than five consecutive cycles and in more than 10 cycles for the other ratios (1:2 and 1:3).

Figure Jump LinkFigure 1. Definition of variables based on flow and Pes tracings. The entrainment duration in this patient was 32.17 s, and the entrainment ratio was 1:2 (one neural cycle every two mechanical cycles). Dotted lines denote the commencement of the mechanical and neural cycles. Ttotmech is the duration, in seconds, of the mechanical cycle, and dP is defined as the interval between the commencement of the mechanical and the neural inspiration. In this example, dP was 0.66 s and Ttotmech was 2.29 s. The phase angle (θ) was calculated as θ = dP/ Ttotmech × 360°, resulting in a value of 104°. dP = phase difference; Pes = esophageal pressure; Ttotmech = ventilator cycle duration.Grahic Jump Location

The dP was defined as the time, in seconds, elapsing between the commencement of the ventilator and the neural breath (Fig 1). The onset of the patient’s neural respiratory activity was determined as the point at which a sudden decrease in Pes or a sudden increase in EAdi was detected. The dP divided by the Ttotmech and multiplied by 360° provided the phase angle (θ), which is the standard way of expressing the relationship between machine and neural respiratory activity onset.3,7

The phase angle (θ) = ([neural onset time − ventilator onset time]/Ttotmech) × 360° (Fig 1). Therefore, a θ of 0° would correspond to neural and ventilator onset coincidence. The degree of entrainment was assessed by the SD and the interquartile range (IQR) (25th-75th quartile) of the different θ, as well as by the CV of Ttotneu. Phase angles were calculated solely in breaths with a clear deviation of Pes or EAdi from the baseline value. Recordings in which patient effort was absent were not included in the analysis. Finally, whenever possible, the inspiratory pressure time product of the inspiratory muscles was calculated as the product of breathing frequency and Pes time integral.13,14

Data were analyzed by descriptive statistical methods and are expressed as mean ± SD, medians, and the IQR, CV, and box plots. Statistical analysis was carried out by SPSS software (version 16.0; IBM).

Patient Characteristics

Recordings of Pes or EAdi activity were available in eight patients. All had a diagnosis of ARDS and were deeply sedated as indicated by the RASS. They were ventilated with either volume assist-control (VAC) or pressure assist-control modes. The ventilators used were Evita XL (Dräger) and Servo-I (MAQUET Holding GmbH & Co KG). An esophageal balloon was inserted into six patients with the objective of selecting ventilator settings according to lung mechanical properties. To optimize monitoring of patient-ventilator synchronization, an EAdi catheter was placed in two patients. The demographic characteristics, diagnosis on admission, ventilator settings, and respiratory system mechanics are shown in Table 1.

Table Graphic Jump Location
Table 1 —Demographic, Clinical, Ventilator, and Respiratory Parameters of the Eight Patients Examined

Crs = respiratory system compliance; F = female; IBW = ideal body weight; M = male; PAC = pressure assist-control; PEEP = positive end-expiratory pressure; P/F = Pao2 to Fio2 ratio; Pplat = plateau airway pressure; RR = respiratory rate; Rrs = respiratory system resistance; SIRS = systemic inflammatory response syndrome; Timech = mechanical inspiratory time; VAC = volume assist-control; Vt = tidal volume.

Entrainment Duration, Observed Patterns, and Phase Angles

All patients demonstrated entrainment for periods varying from 12% to 100% of their recording time (Table 2). The Ttotneu of 1:1 and 1:2 reverse-triggered breaths had a mean (± SD) CV of 2.2% (±0.7%) and 4% (±2.8%), respectively, which was very close to the CV of Ttotmech (0.3% [±0.2%]). Periods of nonentrained efforts (with a CV of Ttotneu of 24.1% [±7.7%]) or absence of inspiratory activity could intervene between entrainment epochs. Box plots of the CV of the Ttotneu of 1:1 and 1:2 reverse-triggered breaths, and the Ttotmech and Ttotneu of nonentrained breaths, are shown in Figure 2.

Table Graphic Jump Location
Table 2 —Sedation Level, Total Recording Time, Entrainment Duration and Ratio, and Arterial Blood Gases in the Eight Patients Tested

RASS = Richmond Agitation and Sedation Scale.

Figure Jump LinkFigure 2. CVs of the cycle durations. Box plots illustrating the median and interquartile range of the CVs of T tot mech, T tot neural 1:1, T tot neural 1:2, and T tot no entrainment. CV is expressed as a percentage. CV = coefficient of variation; T tot mech = cycle duration of mechanical breaths; T tot neural 1:1 = cycle duration of reverse triggered breaths during 1:1 entrainment; T tot neural 1:2 = cycle duration of reverse triggered breaths during 1:2 entrainment; T tot no entrainment = cycle duration of neural nonentrained breaths.Grahic Jump Location

The 1:1 pattern was the dominant entrainment pattern and the more stable one, enduring without interruption for notably long time periods (Table 2). On the other hand, the 1:2 pattern was commonly interrupted, every 10 to 12 cycles, by nonentrainment epochs.

Figure 3 shows representative recordings of the various entrainment patterns. It can be observed that the appearance of a “reverse-triggered effort” encroaching upon the end of mechanical inflation makes its visual recognition extremely difficult in most pressure and flow waveforms recordings. The negative notch in inspiratory Paw signal during pressure assist-control (Fig 3A) and the elimination of the plateau phase during VAC (Fig 3B) denote the commencement of neural breath within the mechanical inflation. In addition, careful inspection of the inspiratory or expiratory flow signal reveals a deviation from its expected passive shape.

Figure Jump LinkFigure 3. Traces of flow, Paw, and Pes or EAdi during respiratory entrainment epochs. A, 1:1 entrainment in a patient ventilated with pressure assist-control. Arrows illustrate the notch on Paw in the presence of the patient’s effort. B, 1:2 entrainment during volume assist-control. Arrows illustrate the notch on flow in the presence of the patient’s effort. C, 1:3 entrainment during pressure assist-control. Arrows illustrate the notch on Paw in the presence of the patient’s effort. Dotted lines indicate the commencement of neural breath. EAdi = diaphragmatic electrical activity; Paw = airway pressure. See Figure 1 legend for expansion of other abbreviations.Grahic Jump Location

The SD of phase angles during 1:1 entrainment periods varied from 4° to 10°, and the angles were wider than those of 1:2 entrained periods (12° to 23°). Box plots of the median and the IQR of phase angles are presented in Figure 4. In general, neural efforts started before the cycling off of the ventilator. In two patients (patients 1 and 8), 63% and 11% of reverse-triggered efforts, respectively, resulted in a mean (± SD) tidal volume (Vt) inflation of 293 ± 161 mL (4 ± 2 mL/kg ideal body weight [IBW]) in the first patient and 400 ± 34 mL (6 ± 0.54 mL/kg IBW) in the second (Figs 5A, 5B). Pressure time product of the inspiratory muscles of the entrained breaths could be reliably estimated in three patients (patients 2, 3, and 8) and their mean values (± SD) were 38 ± 7.2 cm H2O × s/min, 20 ± 4.1 cm H2O × s/min, and 19 ± 8.3 cm H2O × s/min, respectively.

Figure Jump LinkFigure 4. Phase angles. Box plots of θ (median values ± interquartile ranges) during 1:1 (white boxes) and 1:2 (gray boxes) respiratory entrainment of all eight PTs examined. PT = patient.Grahic Jump Location
Figure Jump LinkFigure 5. Tracings of flow, VT, Paw, and Pes in patients 1 and 8, ventilated with pressure assist-control and VAC, respectively. Dotted lines illustrate the beginning of neural efforts. A, Patient 1. During 1:2 entrainment, the patient’s inspiratory efforts did not trigger the ventilator but managed to insert flow into the lungs (arrows) and, thus, increased VT (by 180 mL in this cycle). B, Patient 8. 1:1 entrainment during which the patient’s efforts triggered the ventilator with a sort of “breath stacking” (arrows) generating very high end-inspiratory VT (approximately 800 mL) during the entrained breaths. Double arrow line represents the additional VT (400 mL) insufflated into the lungs by an entrained breath. VT = tidal volume. See Figure 1 and 3 legends for expansion of other abbreviations.Grahic Jump Location
Effects of Changing Ventilator Settings

The ventilator settings were modified in four patients:

  • In patient 1, the 1:3 entrainment ratio was apparent at an initial ventilator frequency (RRvent) of 22 breaths/min. Lowering the machine’s rate to 17 breaths/min, with no other change in ventilator settings, resulted in a 1:2 entrainment ratio that rapidly changed to a 1:1 entrainment ratio.

  • Patient 3 exhibited a stable 1:1 respiratory entrainment during ventilation with VAC at an RRvent of 20 breaths/min. The RRvent was increased to 27 breaths/min, and the neural efforts disappeared.

  • In patient 4, the 1:1 patient-ventilator entrainment pattern was maintained when RRvent was changed from 30 to 26 breaths/min, whereas at a ventilator rate of 21 breaths/min, all cycles were triggered by the patient. With an increase of RRvent to 31 breaths/min, the neural effort ceased. Other ventilator settings remained unchanged during the aforementioned alterations in RRvent. We also examined, in the same patient, the effect of Vt during a stable RRvent of 30 breaths/min. At this RRvent, 1:1 entrainment was apparent at a Vt of 380 mL, whereas an increase of Vt to 500 mL eliminated patient efforts.

  • Finally, patient 5 was mostly recorded under pressure assist-control with the settings shown in Table 1. He exhibited a stable 1:1 entrainment ratio throughout the whole 654 s of recording time. Subsequently, the physician decided to switch the mode to VAC, with an increased RRvent (from 20 to 31 breaths/min) and a decreased Vt (from 8 to 4 mL/kg IBW). During 230 s of recording in VAC with the previous settings, only short-lived 1:1 entrainment periods (six consecutive cycles) could be identified.

Irregularly Distributed Reverse-Triggered Efforts

Time periods elapsed among entrainment intervals during which the neural efforts did not fulfill the previously defined entrainment ratios. These reverse-triggered efforts always appeared at the same θ. These efforts, however, also seemed to be stimulated by the ventilator, albeit in a chaotic manner (Fig 6).

Figure Jump LinkFigure 6. Irregular reverse triggering. Phase angles of sequential neural efforts (gray diamonds) in relation to sequential ventilator breaths (horizontal axis) in one patient during irregular reverse triggering. We can observe that ventilator cycles are accompanied by neural effort in an unstable ratio. Despite their irregular relationship with the ventilator frequency, neural efforts start at around the same phase angle of the mechanical cycle.Grahic Jump Location

In this observational study, we documented the presence of respiratory entrainment in critically ill adults who were mechanically ventilated. We consecutively observed, in eight deeply sedated patients with ARDS, neural efforts entrained by the ventilator at three different ratios: 1:1, 1:2, and 1:3. We defined these neural efforts apparently triggered by the ventilator as “reverse-triggered breaths.” They occurred mainly around the transition phase from mechanical inspiration to expiration, remaining unnoticed by the treating physician. These “reverse-triggered breaths” form a potentially common, yet unclassified, form of patient-ventilator interaction.

Pathophysiologic Mechanisms of Respiratory Entrainment

The pathophysiologic mechanisms of “reverse triggering,” described in the current study, could be related to the phenomenon of respiratory entrainment, reported only in animals,4,5,9,11,15,16 healthy humans,3,6,7 and preterm infants.17,18 As in the recovery of rhythmic limb motor movements after peripheral stimulation in spinal cord-injured cats, afferent inputs seem to play a critical role on entrainment generation.19,20 Failure in the reproduction of the phenomenon in anesthetized animals after bilateral vagotomy has emphasized that slowly adapting stretch receptors, responsible for the Hering-Breuer reflexes, are essential for respiratory entrainment mechanisms.5,11,15 Despite its fundamental role, the Hering-Breuer reflex is not the only factor implicated in entrainment phenomena.

Entrainment can be observed after vagal cooling in animals and in healthy subjects who have undergone a lung transplant. In these scenarios, however, there is a wider distribution around each phase angle and a more limited ventilator rate range.6,9 Rapidly adapting receptors and vagal C fibers, along with cortical and subcortical influences, also seem to be responsible for respiratory rhythm entrainment to the ventilator.

Methodologic Aspects

We initially defined entrainment visually, based on the inspection of available recordings, and, provided that entrainment periods were evident, we proceeded to phase angles calculation. The strength of the entrainment was assessed by the SD and the IQR of the phase angles and, additionally, by the variability of the Ttotneu. Because respiratory entrainment has not yet been classified formally and various periods or cycle-based definitions have been adopted, we reasoned that the 1:1 entrainment had to be present for a minimum of five consecutive cycles and more complex patterns (ie, 1:2 and 1:3) for a minimum of 10 cycles for entrainment to be characterized as stable.4,7,9,16,17

Characteristics of Reverse Triggering

Entrainment periods of variable duration and ratios were observed in all consecutive patients studied, causing regular reverse triggering. Our recordings were not specifically performed for this purpose, and one may thus hypothesize that the phenomenon is frequent in sedated patients, though scarcely recognized under mechanical ventilation. Indeed, respiratory entrainment could be reproduced in studies conducted in animals and normal subjects. The true incidence of the phenomenon in the ICU setting needs to be studied.

We believe that the fact that all patients in the current study had ARDS possibly reflects (1) the physician’s decision to monitor respiratory mechanics and neural efforts in this specific group of patients rather than an association between ARDS and entrainment phenomena, and (2) that this is a group of patients often receiving high doses of sedatives. To what extent the type of critical illness and the magnitude of respiratory mechanics’ compromise promote reverse triggering remains to be explored.

All patients were deeply sedated as suggested by the low RASS score. Simon et al7 investigated the effect of the wake state and found that wakefulness and anesthesia, in contrast to non-rapid eye movement sleep, broadened the range of machine frequencies at which the 1:1 entrainment occurred. In this study, the only one evaluating the effect of the wake state, the authors suggested that cortical influences facilitate the resetting of the respiratory rhythm to maintain 1:1 entrainment (the patient modified the rhythm to increase comfort when ventilated). It is possible, however, that stronger cortical influences such as pain or agitation could lead to patient-triggered cycles through neural efforts enhancement. In other words, the phenomenon might be present but obscured in awake patients with strong behavioral responses and more obvious in sedated patients. Therefore, sedation in the current study could either promote entrainment phenomena, as suggested by Simon et al,7 and/or make them more apparent.

In accordance with the literature in healthy subjects, 1:1 was the most frequent and stable entrainment ratio recorded.3,4,10,21,22 Graves et al3 reported that rarely noticed complex ratios (2:1, 3:1, and so forth) were more transient, being disrupted every seven to 15 cycles by irregular patterns. Indeed, in our study, 1:2 entrainment was not steady, and nonentrainment periods were interspersed between 1:2 patterns. Moreover, the SDs of 1:2 entrainment phase angles were considerably higher than those of 1:1, implying a less tight entrainment pattern. Only one patient exhibited 1:3 entrainment for a brief period of 25 s before rapidly switching to 1:2.

Additionally, in our study, the ventilator rate was modified in three patients without any other change in ventilator settings and in one patient concomitantly with other changes. In general, increasing the respiratory rate on the ventilator changed the entrainment characteristics (from 1:1 to 1:3 ratios) or abolished entrainment. In patient 5, the increase in RRvent was associated with a reduction in Vt and probably in alveolar ventilation; despite this, the increase in rate was associated with less entrainment. A more systematic assessment would be necessary, however, to understand the influence of the different settings.

We did not measure Paco2, and the aforementioned changes in entrainment characteristics were observed within 1 to 2 min after each modification of the ventilator settings. Thus, it is difficult to determine the precise role of Paco2. Simon et al7 evaluated the effect of Paco2 in entrainment phenomena and found that mild increases in respiratory drive caused by CO2 stimulation did not affect entrainment responses. Nevertheless, it is not clear whether greater changes in Paco2 or acidosis could affect entrainment through powerful effects on the respiratory drive.

In one patient, entrained breaths triggered the ventilator at the end of each passive inflation, thereby doubling the inspired Vt (Fig 5B). This appeared as a “double triggering,” although the triggering mechanism differed for the two breaths. How the physician can abolish such an undesirable effect by modifying the ventilator settings cannot be answered based solely on our results. Previous studies have shown that entrainment is affected by changes in RRvent and Vt.3,17 In newborn infants, 1:1 entrainment has been achieved at ventilator rates close to spontaneous breathing.17,23-25 In anesthetized humans, 1:1 entrainment was maintained at a range of machine inflations ± 40% of the subject’s spontaneous breathing frequencies and at mechanical Vt between 40% and 140% of the patient’s spontaneous Vt.3 In vagally intact animals and humans, when the machine frequency was reduced to below the spontaneous breathing rate, neural efforts preceded the onset of mechanical inflations and the spontaneous rate decreased.3,5,7 Finally, as the RRvent decreased progressively to well below the patient’s spontaneous rate, 1:1 entrainment bifurcated into 1:2 entrainment.3,7 Therefore, in some cases, decreasing the machine rate in a patient may reduce the spontaneous breathing rate and change the entrainment ratio and the phase angle, thereby abolishing high Vt inflations. The few observations made in the patients suggest that entrainment occurs within a certain range of frequencies, above which the patient may be hyperventilated and below which hypoventilation may increase respiratory drive. The direct consequences of the reverse triggering will then depend on the phase angle.

Another important observation is that among entrainment epochs, periods of irregular patient-ventilator ratios occurred, whereas all neural efforts had a consistent coupling interval with the ventilator (approximately the same θ), despite their regular patient-ventilator ratios. Such neural breaths have not been described in the literature. Similar to regular reverse-triggered efforts, they occurred before or around the transition phase from mechanical inflation to passive expiration. In most cases, the physician in charge regarded the patient as entirely passively ventilated.

Clinical Relevance

The phenomenon of respiratory entrainment could be clinically important in critically ill patients in many ways. First, understanding the physiologic mechanisms of entrainment is linked to comprehension of patient-ventilator interaction. A 1:1 entrainment (defined also as harmonic entrainment)4,9 with a very low θ, for example, virtually resembles patient-ventilator synchronization (at least regarding the triggering phase). On the other hand, a lack of respiratory entrainment, a more complex entrainment pattern, or patients with a higher θ all constitute different forms of patient-ventilator asynchrony.

Second, whether the loss of respiratory entrainment is associated with the severity of critical illness has never been explored. On the one hand, the ability of the brain stem to entrain the respiratory rhythm to periodic mechanical inflations is considered a normal phenomenon steadily reproduced experimentally in vagally intact humans and animals. It seems to reflect the ability of the central controller to adapt its output to afferent information. In addition, the positive impact of wakefulness to 1:1 entrainment has been interpreted by Simon et al7 as an adaptive strategy to avoid discomfort during mechanical ventilation. On the other hand, respiratory entrainment indicates a loss of breathing variability.26 Preservation of breathing variability has been linked to improvement of oxygenation and weaning success.27-30 Prospective studies are needed to investigate the prognostic significance of entrainment in patients in the ICU.

Finally, although partially assisted ventilator modes are commonly applied in critically ill patients with the aim of minimizing respiratory muscle activity, reverse-triggered efforts were evident in all patients examined. The consequences of this asynchrony are potentially large. This may indeed continuously induce pliometric contractions of the diaphragm. These contractions are associated with muscle cytokine release and muscle fiber damage. They also induce increased respiratory muscle work and oxygen consumption, may contribute to cardiovascular instability, and make monitoring of the plateau pressure very misleading.30-34 Moreover, reverse-triggered efforts may generate higher plateau pressure in VAC and large Vt and transpulmonary pressure swings during pressure assist-control. In a study by Papazian et al,35 the administration of neuromuscular blocking agents early in the course of severe ARDS was associated with improved survival and more ventilator-free days. In this study, all patients were ventilated with VAC, and a significantly higher number of patients in the placebo group developed a pneumothorax. One hypothesis to explain the results of this study is the potentially deleterious effects of neural efforts despite the fact that lung protective ventilation was applied. Reverse triggering could play a role in this setting.

Unresolved Issues

Several unresolved issues arise from our study, whose small sample size and observational character limit the analysis. Crucial questions include the incidence of entrainment, its various forms, its physiologic mechanism, and the clinical impact on patients in the ICU. The impact of modifying the rate, amplitude, and timing of mechanical inflation, the influence of chemical feedback (Pao2, Paco2, pH), the sedation level and its type, and whether this is a form of peripheral receptor or central controller dysfunction are all largely unknown. Finally, whether the physician can take advantage of respiratory entrainment to optimize patient-ventilator interaction has not been explored.

In this observational study, we documented, for the first time to our knowledge, the presence of “reverse triggering” in deeply sedated, critically ill adult patients under volume or pressure assist-control mechanical ventilation for ARDS. In the context of entrainment, “reverse-triggered” breaths constitute an unclassified and unrecognized form of patient-ventilator interaction. They can be totally overlooked, leading to erroneous assumptions regarding the patient’s respiratory status. The description of this phenomenon represents a step forward in the comprehension of the complex mechanisms dictating the patient-ventilator relationship. Further prospective studies are needed to explore in detail the phenomenon and its consequences in the ICU setting.

Author contributions: Dr Richard is the guarantor of the manuscript and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Dr Akoumianaki: contributed to the identification of the phenomenon, data recording, data analysis and interpretation, and writing of the manuscript.

Dr Lyazidi: contributed to the data collection, statistical analysis, creation of images and tables, and review of the manuscript.

Dr Rey: contributed to the recruitment of patients, data interpretation, and revision of the manuscript.

Dr Matamis: contributed to the data interpretation and revision of the manuscript.

Dr Perez-Martinez: contributed the data collection, data analysis, and revision of the manuscript.

Dr Giraud: contributed to the recruitment of patients and review of the manuscript.

Dr Mancebo: contributed to the provision of feedback on the manuscript.

Dr Brochard: contributed to the scientific guidance for the project, study design, data interpretation, and revision of the manuscript.

Dr Richard: contributed to the identification of the phenomenon, study design, results interpretation, and revision of the manuscript.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Brochard’s research laboratory has received grants from several ventilator companies for specific research projects over the last five years (MAQUET, NAVA; Covidien AG, PAV; Dräger, SmartCare; Philips Respironics, NIV; General Electric, FRC). The remaining author report no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

CV

coefficient of variation

dP

phase difference

EAdi

diaphragmatic electrical activity

IBW

ideal body weight

IQR

interquartile range

Paw

airway pressure

Pes

esophageal pressure

RASS

Richmond Agitation-Sedation Scale

RRvent

ventilator frequency

Ttotmech

ventilator cycle duration

Ttotneu

neural respiratory time

VAC

volume assist-control

Vt

tidal volume

Georgopoulos D. Effects of Mechanical ventilation on control of breathing.. In:Tobin MJ., ed. Principles and Practice of Mechanical Ventilation. New York, NY: Mc Graw-Hill; 2006;:715-728.
 
Baconnier PF, Benchetrit G, Pachot P, Demongeot J. Entrainment of the respiratory rhythm: a new approach. J Theor Biol. 1993;164(2):149-162. [CrossRef] [PubMed]
 
Graves C, Glass L, Laporta D, Meloche R, Grassino A. Respiratory phase locking during mechanical ventilation in anesthetized human subjects. Am J Physiol. 1986;250(5 pt 2):R902-R909. [PubMed]
 
Muzzin S, Baconnier P, Benchetrit G. Entrainment of respiratory rhythm by periodic lung inflation: effect of airflow rate and duration. Am J Physiol. 1992;263(2 pt 2):R292-R300. [PubMed]
 
Petrillo GA, Glass L, Trippenbach T. Phase locking of the respiratory rhythm in cats to a mechanical ventilator. Can J Physiol Pharmacol. 1983;61(6):599-607. [CrossRef] [PubMed]
 
Simon PM, Habel AM, Daubenspeck JA, Leiter JC. Vagal feedback in the entrainment of respiration to mechanical ventilation in sleeping humans. J Appl Physiol. 2000;89(2):760-769. [PubMed]
 
Simon PM, Zurob AS, Wies WM, Leiter JC, Hubmayr RD. Entrainment of respiration in humans by periodic lung inflations. Effect of state and CO2Am J Respir Crit Care Med. 1999;160(3):950-960. [PubMed]
 
Pisarri TE, Yu J, Coleridge HM, Coleridge JC. Background activity in pulmonary vagal C-fibers and its effects on breathing. Respir Physiol. 1986;64(1):29-43. [CrossRef] [PubMed]
 
Muzzin S, Trippenbach T, Baconnier P, Benchetrit G. Entrainment of the respiratory rhythm by periodic lung inflation during vagal cooling. Respir Physiol. 1989;75(2):157-172. [CrossRef] [PubMed]
 
Petrillo GA, Glass L. A theory for phase locking of respiration in cats to a mechanical ventilator. Am J Physiol. 1984;246(3 pt 2):R311-R320. [PubMed]
 
Vibert JF, Caille D, Segundo JP. Respiratory oscillator entrainment by periodic vagal afferentes: an experimental test of a model. Biol Cybern. 1981;41(2):119-130. [CrossRef] [PubMed]
 
Sessler CN, Gosnell MS, Grap MJ, et al. The Richmond Agitation-Sedation Scale: validity and reliability in adult intensive care unit patients. Am J Respir Crit Care Med. 2002;166(10):1338-1344. [CrossRef] [PubMed]
 
Sassoon CS, Light RW, Lodia R, Sieck GC, Mahutte CK. Pressure-time product during continuous positive airway pressure, pressure support ventilation, and T-piece during weaning from mechanical ventilation. Am Rev Respir Dis. 1991;143(3):469-475. [PubMed]
 
Aslanian P, El Atrous S, Isabey D, et al. Effects of flow triggering on breathing effort during partial ventilatory support. Am J Respir Crit Care Med. 1998;157(1):135-143. [PubMed]
 
Mühlemann R, Fallert M. Hering-Breuer reflex during artificial respiration in the rabbit. II. Relfex blocking by stepwise vagal cooling [in German]. Pflugers Arch. 1971;330(2):175-188. [CrossRef] [PubMed]
 
MacDonald SM, Song G, Poon CS. Nonassociative learning promotes respiratory entrainment to mechanical ventilation. PLoS ONE. 2007;2(9):e865. [CrossRef] [PubMed]
 
Bignall S, Kitney RI, Summers D. Use of the frequency-tracking locus in estimating the degree of respiratory entrainment in preterm infants. Physiol Meas. 1993;14(4):441-454. [CrossRef] [PubMed]
 
Bignall S, Summers D. Effects of intermittent mandatory ventilation on respiratory timing in preterm infants. Early Hum Dev. 1994;36(3):175-186. [CrossRef] [PubMed]
 
Barrière G, Leblond H, Provencher J, Rossignol S. Prominent role of the spinal central pattern generator in the recovery of locomotion after partial spinal cord injuries. J Neurosci. 2008;28(15):3976-3987. [CrossRef] [PubMed]
 
Duysens J, Van de Crommert HW. Neural control of locomotion; the central pattern generator from cats to humans. Gait Posture. 1998;7(2):131-141. [CrossRef] [PubMed]
 
Benchetrit G, Muzzin S, Baconnier P, Bachy JP, Eberhard A. Entrainment of the respiratory rhythm by repetitive stimulation of pulmonary receptors: effect of CO2.. In:vonEuler C, Lagercrantz H., eds. Neurobiology of the Control of Breathing. New York, NY: Raven Press; 1986;:263-268.
 
Rodenstein DO, Stănescu DC, Cuttita G, Liistro G, Veriter C. Ventilatory and diaphragmatic EMG responses to negative-pressure ventilation in airflow obstruction. J Appl Physiol. 1988;65(4):1621-1626. [PubMed]
 
Amitay M, Etches PC, Finer NN, Maidens JM. Synchronous mechanical ventilation of the neonate with respiratory disease. Crit Care Med. 1993;21(1):118-124. [CrossRef] [PubMed]
 
Greenough A, Morley CJ, Pool J. Fighting the ventilator—are fast rates an effective alternative to paralysis?. Early Hum Dev. 1986;13(2):189-194. [CrossRef] [PubMed]
 
South M, Morley CJ. Synchronous mechanical ventilation of the neonate. Arch Dis Child. 1986;61(12):1190-1195. [CrossRef] [PubMed]
 
Tobin MJ, Mador MJ, Guenther SM, Lodato RF, Sackner MA. Variability of resting respiratory drive and timing in healthy subjects. J Appl Physiol. 1988;65(1):309-317. [PubMed]
 
Brack T, Jubran A, Tobin MJ. Effect of elastic loading on variational activity of breathing. Am J Respir Crit Care Med. 1997;155(4):1341-1348. [PubMed]
 
Brack T, Jubran A, Tobin MJ. Effect of resistive loading on variational activity of breathing. Am J Respir Crit Care Med. 1998;157(6 pt 1):1756-1763. [PubMed]
 
Brack T, Jubran A, Tobin MJ. Dyspnea and decreased variability of breathing in patients with restrictive lung disease. Am J Respir Crit Care Med. 2002;165(9):1260-1264. [CrossRef] [PubMed]
 
Wysocki M, Cracco C, Teixeira A, et al. Reduced breathing variability as a predictor of unsuccessful patient separation from mechanical ventilation. Crit Care Med. 2006;34(8):2076-2083. [CrossRef] [PubMed]
 
Fridén J, Sjöström M, Ekblom B. Myofibrillar damage following intense eccentric exercise in man. Int J Sports Med. 1983;4(3):170-176. [CrossRef] [PubMed]
 
Hirose L, Nosaka K, Newton M, et al. Changes in inflammatory mediators following eccentric exercise of the elbow flexors. Exerc Immunol Rev. 2004;10:75-90. [PubMed]
 
Sorichter S, Puschendorf B, Mair J. Skeletal muscle injury induced by eccentric muscle action: muscle proteins as markers of muscle fiber injury. Exerc Immunol Rev. 1999;5:5-21. [PubMed]
 
Thille AW, Rodriguez P, Cabello B, Lellouche F, Brochard L. Patient-ventilator asynchrony during assisted mechanical ventilation. Intensive Care Med. 2006;32(10):1515-1522. [CrossRef] [PubMed]
 
Papazian L, Forel JM, Gacouin A, et al;; ACURASYS Study Investigators ACURASYS Study Investigators. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med. 2010;363(12):1107-1116. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1. Definition of variables based on flow and Pes tracings. The entrainment duration in this patient was 32.17 s, and the entrainment ratio was 1:2 (one neural cycle every two mechanical cycles). Dotted lines denote the commencement of the mechanical and neural cycles. Ttotmech is the duration, in seconds, of the mechanical cycle, and dP is defined as the interval between the commencement of the mechanical and the neural inspiration. In this example, dP was 0.66 s and Ttotmech was 2.29 s. The phase angle (θ) was calculated as θ = dP/ Ttotmech × 360°, resulting in a value of 104°. dP = phase difference; Pes = esophageal pressure; Ttotmech = ventilator cycle duration.Grahic Jump Location
Figure Jump LinkFigure 2. CVs of the cycle durations. Box plots illustrating the median and interquartile range of the CVs of T tot mech, T tot neural 1:1, T tot neural 1:2, and T tot no entrainment. CV is expressed as a percentage. CV = coefficient of variation; T tot mech = cycle duration of mechanical breaths; T tot neural 1:1 = cycle duration of reverse triggered breaths during 1:1 entrainment; T tot neural 1:2 = cycle duration of reverse triggered breaths during 1:2 entrainment; T tot no entrainment = cycle duration of neural nonentrained breaths.Grahic Jump Location
Figure Jump LinkFigure 3. Traces of flow, Paw, and Pes or EAdi during respiratory entrainment epochs. A, 1:1 entrainment in a patient ventilated with pressure assist-control. Arrows illustrate the notch on Paw in the presence of the patient’s effort. B, 1:2 entrainment during volume assist-control. Arrows illustrate the notch on flow in the presence of the patient’s effort. C, 1:3 entrainment during pressure assist-control. Arrows illustrate the notch on Paw in the presence of the patient’s effort. Dotted lines indicate the commencement of neural breath. EAdi = diaphragmatic electrical activity; Paw = airway pressure. See Figure 1 legend for expansion of other abbreviations.Grahic Jump Location
Figure Jump LinkFigure 4. Phase angles. Box plots of θ (median values ± interquartile ranges) during 1:1 (white boxes) and 1:2 (gray boxes) respiratory entrainment of all eight PTs examined. PT = patient.Grahic Jump Location
Figure Jump LinkFigure 5. Tracings of flow, VT, Paw, and Pes in patients 1 and 8, ventilated with pressure assist-control and VAC, respectively. Dotted lines illustrate the beginning of neural efforts. A, Patient 1. During 1:2 entrainment, the patient’s inspiratory efforts did not trigger the ventilator but managed to insert flow into the lungs (arrows) and, thus, increased VT (by 180 mL in this cycle). B, Patient 8. 1:1 entrainment during which the patient’s efforts triggered the ventilator with a sort of “breath stacking” (arrows) generating very high end-inspiratory VT (approximately 800 mL) during the entrained breaths. Double arrow line represents the additional VT (400 mL) insufflated into the lungs by an entrained breath. VT = tidal volume. See Figure 1 and 3 legends for expansion of other abbreviations.Grahic Jump Location
Figure Jump LinkFigure 6. Irregular reverse triggering. Phase angles of sequential neural efforts (gray diamonds) in relation to sequential ventilator breaths (horizontal axis) in one patient during irregular reverse triggering. We can observe that ventilator cycles are accompanied by neural effort in an unstable ratio. Despite their irregular relationship with the ventilator frequency, neural efforts start at around the same phase angle of the mechanical cycle.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 —Demographic, Clinical, Ventilator, and Respiratory Parameters of the Eight Patients Examined

Crs = respiratory system compliance; F = female; IBW = ideal body weight; M = male; PAC = pressure assist-control; PEEP = positive end-expiratory pressure; P/F = Pao2 to Fio2 ratio; Pplat = plateau airway pressure; RR = respiratory rate; Rrs = respiratory system resistance; SIRS = systemic inflammatory response syndrome; Timech = mechanical inspiratory time; VAC = volume assist-control; Vt = tidal volume.

Table Graphic Jump Location
Table 2 —Sedation Level, Total Recording Time, Entrainment Duration and Ratio, and Arterial Blood Gases in the Eight Patients Tested

RASS = Richmond Agitation and Sedation Scale.

References

Georgopoulos D. Effects of Mechanical ventilation on control of breathing.. In:Tobin MJ., ed. Principles and Practice of Mechanical Ventilation. New York, NY: Mc Graw-Hill; 2006;:715-728.
 
Baconnier PF, Benchetrit G, Pachot P, Demongeot J. Entrainment of the respiratory rhythm: a new approach. J Theor Biol. 1993;164(2):149-162. [CrossRef] [PubMed]
 
Graves C, Glass L, Laporta D, Meloche R, Grassino A. Respiratory phase locking during mechanical ventilation in anesthetized human subjects. Am J Physiol. 1986;250(5 pt 2):R902-R909. [PubMed]
 
Muzzin S, Baconnier P, Benchetrit G. Entrainment of respiratory rhythm by periodic lung inflation: effect of airflow rate and duration. Am J Physiol. 1992;263(2 pt 2):R292-R300. [PubMed]
 
Petrillo GA, Glass L, Trippenbach T. Phase locking of the respiratory rhythm in cats to a mechanical ventilator. Can J Physiol Pharmacol. 1983;61(6):599-607. [CrossRef] [PubMed]
 
Simon PM, Habel AM, Daubenspeck JA, Leiter JC. Vagal feedback in the entrainment of respiration to mechanical ventilation in sleeping humans. J Appl Physiol. 2000;89(2):760-769. [PubMed]
 
Simon PM, Zurob AS, Wies WM, Leiter JC, Hubmayr RD. Entrainment of respiration in humans by periodic lung inflations. Effect of state and CO2Am J Respir Crit Care Med. 1999;160(3):950-960. [PubMed]
 
Pisarri TE, Yu J, Coleridge HM, Coleridge JC. Background activity in pulmonary vagal C-fibers and its effects on breathing. Respir Physiol. 1986;64(1):29-43. [CrossRef] [PubMed]
 
Muzzin S, Trippenbach T, Baconnier P, Benchetrit G. Entrainment of the respiratory rhythm by periodic lung inflation during vagal cooling. Respir Physiol. 1989;75(2):157-172. [CrossRef] [PubMed]
 
Petrillo GA, Glass L. A theory for phase locking of respiration in cats to a mechanical ventilator. Am J Physiol. 1984;246(3 pt 2):R311-R320. [PubMed]
 
Vibert JF, Caille D, Segundo JP. Respiratory oscillator entrainment by periodic vagal afferentes: an experimental test of a model. Biol Cybern. 1981;41(2):119-130. [CrossRef] [PubMed]
 
Sessler CN, Gosnell MS, Grap MJ, et al. The Richmond Agitation-Sedation Scale: validity and reliability in adult intensive care unit patients. Am J Respir Crit Care Med. 2002;166(10):1338-1344. [CrossRef] [PubMed]
 
Sassoon CS, Light RW, Lodia R, Sieck GC, Mahutte CK. Pressure-time product during continuous positive airway pressure, pressure support ventilation, and T-piece during weaning from mechanical ventilation. Am Rev Respir Dis. 1991;143(3):469-475. [PubMed]
 
Aslanian P, El Atrous S, Isabey D, et al. Effects of flow triggering on breathing effort during partial ventilatory support. Am J Respir Crit Care Med. 1998;157(1):135-143. [PubMed]
 
Mühlemann R, Fallert M. Hering-Breuer reflex during artificial respiration in the rabbit. II. Relfex blocking by stepwise vagal cooling [in German]. Pflugers Arch. 1971;330(2):175-188. [CrossRef] [PubMed]
 
MacDonald SM, Song G, Poon CS. Nonassociative learning promotes respiratory entrainment to mechanical ventilation. PLoS ONE. 2007;2(9):e865. [CrossRef] [PubMed]
 
Bignall S, Kitney RI, Summers D. Use of the frequency-tracking locus in estimating the degree of respiratory entrainment in preterm infants. Physiol Meas. 1993;14(4):441-454. [CrossRef] [PubMed]
 
Bignall S, Summers D. Effects of intermittent mandatory ventilation on respiratory timing in preterm infants. Early Hum Dev. 1994;36(3):175-186. [CrossRef] [PubMed]
 
Barrière G, Leblond H, Provencher J, Rossignol S. Prominent role of the spinal central pattern generator in the recovery of locomotion after partial spinal cord injuries. J Neurosci. 2008;28(15):3976-3987. [CrossRef] [PubMed]
 
Duysens J, Van de Crommert HW. Neural control of locomotion; the central pattern generator from cats to humans. Gait Posture. 1998;7(2):131-141. [CrossRef] [PubMed]
 
Benchetrit G, Muzzin S, Baconnier P, Bachy JP, Eberhard A. Entrainment of the respiratory rhythm by repetitive stimulation of pulmonary receptors: effect of CO2.. In:vonEuler C, Lagercrantz H., eds. Neurobiology of the Control of Breathing. New York, NY: Raven Press; 1986;:263-268.
 
Rodenstein DO, Stănescu DC, Cuttita G, Liistro G, Veriter C. Ventilatory and diaphragmatic EMG responses to negative-pressure ventilation in airflow obstruction. J Appl Physiol. 1988;65(4):1621-1626. [PubMed]
 
Amitay M, Etches PC, Finer NN, Maidens JM. Synchronous mechanical ventilation of the neonate with respiratory disease. Crit Care Med. 1993;21(1):118-124. [CrossRef] [PubMed]
 
Greenough A, Morley CJ, Pool J. Fighting the ventilator—are fast rates an effective alternative to paralysis?. Early Hum Dev. 1986;13(2):189-194. [CrossRef] [PubMed]
 
South M, Morley CJ. Synchronous mechanical ventilation of the neonate. Arch Dis Child. 1986;61(12):1190-1195. [CrossRef] [PubMed]
 
Tobin MJ, Mador MJ, Guenther SM, Lodato RF, Sackner MA. Variability of resting respiratory drive and timing in healthy subjects. J Appl Physiol. 1988;65(1):309-317. [PubMed]
 
Brack T, Jubran A, Tobin MJ. Effect of elastic loading on variational activity of breathing. Am J Respir Crit Care Med. 1997;155(4):1341-1348. [PubMed]
 
Brack T, Jubran A, Tobin MJ. Effect of resistive loading on variational activity of breathing. Am J Respir Crit Care Med. 1998;157(6 pt 1):1756-1763. [PubMed]
 
Brack T, Jubran A, Tobin MJ. Dyspnea and decreased variability of breathing in patients with restrictive lung disease. Am J Respir Crit Care Med. 2002;165(9):1260-1264. [CrossRef] [PubMed]
 
Wysocki M, Cracco C, Teixeira A, et al. Reduced breathing variability as a predictor of unsuccessful patient separation from mechanical ventilation. Crit Care Med. 2006;34(8):2076-2083. [CrossRef] [PubMed]
 
Fridén J, Sjöström M, Ekblom B. Myofibrillar damage following intense eccentric exercise in man. Int J Sports Med. 1983;4(3):170-176. [CrossRef] [PubMed]
 
Hirose L, Nosaka K, Newton M, et al. Changes in inflammatory mediators following eccentric exercise of the elbow flexors. Exerc Immunol Rev. 2004;10:75-90. [PubMed]
 
Sorichter S, Puschendorf B, Mair J. Skeletal muscle injury induced by eccentric muscle action: muscle proteins as markers of muscle fiber injury. Exerc Immunol Rev. 1999;5:5-21. [PubMed]
 
Thille AW, Rodriguez P, Cabello B, Lellouche F, Brochard L. Patient-ventilator asynchrony during assisted mechanical ventilation. Intensive Care Med. 2006;32(10):1515-1522. [CrossRef] [PubMed]
 
Papazian L, Forel JM, Gacouin A, et al;; ACURASYS Study Investigators ACURASYS Study Investigators. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med. 2010;363(12):1107-1116. [CrossRef] [PubMed]
 
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

CHEST Journal Articles
CHEST Collections
Guidelines
  • CHEST Journal
    Print ISSN: 0012-3692
    Online ISSN: 1931-3543