Reverse triggering dyssynchrony and its impact on diaphragm injury during mechanical ventilation.

Mechanical ventilation (MV) is used to sustain life in patients admitted to the intensive care unit for a wide spectrum of indications such as elective surgical procedures, septic shock, multiple organic failure and acute respiratory distress syndrome. Safe and effective ventilation depends on a smooth interaction between these two independent systems: the patient and the mechanical ventilator. Any mismatch between the patient and mechanical ventilator in terms of breath delivery timing, as well as the inability of the ventilator’s flow delivery to match the patient’s flow demand, is referred to as patient-ventilator dyssynchrony (PVD). Reverse Triggering (RT) is a type of PVD where muscle contractions are delayed, starting a certain amount of time after the machine triggered breath and occurring under different entrainment patterns. RT was originally described in 2013, in sedated patients admitted to the intensive care unit. Unfortunately, data about RT until now is scarce and its relevance remains totally uncertain. If any, the relevance of RT might be attributed to 2 main factors: the frequency of this PVD and its potential consequences in both lung and diaphragm injury. The group of different adverse patient–ventilator interactions leading to diaphragm atrophy and injury and resulting in a final common pathway of diaphragm weakness are denominated myotrauma. Particularly, RT is thought to cause eccentric myotrauma, which is a muscle contraction while muscle is lengthening during the ventilator’s expiratory phase while lung volume is decreasing. Based on animal and human studies, the impact of RT (if any) might be mediated by the level of breathing effort. In this thesis we aimed to describe the incidence of RT in patients early after intubation and admission to the intensive care unit and also to study the impact of RT with different levels of breathing effort on diaphragm injury (function and structure) in an animal model of RT with acute respiratory distress syndrome. To determine RT incidence, we conducted ancillary study in patients with continuous monitorization of the electrical activity of the diaphragm (EAdi). We developed a method for automatic detection of reverse triggering using EAdi and airway pressure curve. We additionally compared patients’ demographics, sedation depth and ventilation settings according to the median rate of reverse triggering, including time to transition to assisted ventilation or extubation. We found that our new automatic method presented a good diagnostic accuracy (98% total accuracy). Using a threshold of 1 µV for EAdi, median reverse triggering rate was 8% (range 0.1 to 75) with 44% (17 out of 39) of patients having ≥10% of breaths with reverse triggering. With 3 µV threshold, 26% (10 out of 39) of patients had ≥10% reverse triggered breaths. Importantly, patients who resented more reverse triggering were more likely to be on an assisted mode or extubated in the following 24 hours than patients who had low rate of RT (68% vs 35%; p=0.039). We also developed a 3 hours model of reverse triggering in pigs by modifying tidal volume, respiratory rate and level of sedation. Our approach to induce reverse triggering was not only feasible, but consistently reproducible in all animals, although with different presentations in terms of breathing effort and entrainment pattern. The most frequent entrainment pattern observed was 1:1, occurring in 83% of the total animals. Compared to passive ventilation (no breathing effort), RT group had significantly lower tidal volume (7 vs 10 ml/kg) and higher respiratory rate (45 vs 31 bpm) whereas no differences were found in other cardiorespiratory and sedation variables, nor in lung injury indicators after the study period. In order to study the impact of RT on diaphragm injury, we divided the RT group in 3 subgroups based on the level of breathing effort calculated by the pressure time product. Thus, 4 experimental groups were analyzed: Passive (no breathing effort), RT with low effort, RT with middle effort and RT with high effort. Function of the diaphragm was assessed by the ability to generate force, which correspond to the transdiaphragmatic pressure whilst diaphragm structure was evaluated using histological samples and serum troponin I as biomarker of muscle injury. We found that RT affects diaphragm function in two opposite directions. On one hand, animals with RT and low breathing effort showed a significant increase in force of 10% as compared to baseline. On the other hand, animals with RT and high breathing effort showed a larger decrease in force (34%) as compared to baseline. This difference was significantly different with the other experimental groups. Moreover, histologic analysis of diaphragm myofibers showed that RT with high breathing effort had significant lower myofiber cross-sectional area than passive group. Also, when comparing abnormal myofibers between groups, a significantly lower proportion of small fiber size were found in RT whit high breathing effort in comparison to passive group. No differences were found in serum troponin I neither overtime nor between groups. In conclusion, an EAdi-based automated reverse triggering detection showed that this asynchrony is highly prevalent early after intubation under assist-control ventilation; the incidence depends on the magnitude of the activity detected and that reverse triggering seems to occur during the transition phase between deep sedation and the onset of patient triggering. In addition, the creation of a reverse triggering model revealed this phenomenon very complex, with high variability in terms of entrainment pattern and level of breathing effort. Finally, we have confirmed that RT dyssynchrony affects diaphragm function and this effect is modulated by the level of respiratory effort. Reverse triggering with low breathing effort seems to have a protective role on diaphragm function whereas reverse triggering with high breathing effort may favor eccentric myotrauma.Mechanical ventilation (MV) is used to sustain life in patients admitted to the intensive care unit for a wide spectrum of indications such as elective surgical procedures, septic shock, multiple organic failure and acute respiratory distress syndrome. Safe and effective ventilation depends on a smooth interaction between these two independent systems: the patient and the mechanical ventilator. Any mismatch between the patient and mechanical ventilator in terms of breath delivery timing, as well as the inability of the ventilator’s flow delivery to match the patient’s flow demand, is referred to as patient-ventilator dyssynchrony (PVD). Reverse Triggering (RT) is a type of PVD where muscle contractions are delayed, starting a certain amount of time after the machine triggered breath and occurring under different entrainment patterns. RT was originally described in 2013, in sedated patients admitted to the intensive care unit. Unfortunately, data about RT until now is scarce and its relevance remains totally uncertain. If any, the relevance of RT might be attributed to 2 main factors: the frequency of this PVD and its potential consequences in both lung and diaphragm injury. The group of different adverse patient–ventilator interactions leading to diaphragm atrophy and injury and resulting in a final common pathway of diaphragm weakness are denominated myotrauma. Particularly, RT is thought to cause eccentric myotrauma, which is a muscle contraction while muscle is lengthening during the ventilator’s expiratory phase while lung volume is decreasing. Based on animal and human studies, the impact of RT (if any) might be mediated by the level of breathing effort. In this thesis we aimed to describe the incidence of RT in patients early after intubation and admission to the intensive care unit and also to study the impact of RT with different levels of breathing effort on diaphragm injury (function and structure) in an animal model of RT with acute respiratory distress syndrome. To determine RT incidence, we conducted ancillary study in patients with continuous monitorization of the electrical activity of the diaphragm (EAdi). We developed a method for automatic detection of reverse triggering using EAdi and airway pressure curve. We additionally compared patients’ demographics, sedation depth and ventilation settings according to the median rate of reverse triggering, including time to transition to assisted ventilation or extubation. We found that our new automatic method presented a good diagnostic accuracy (98% total accuracy). Using a threshold of 1 µV for EAdi, median reverse triggering rate was 8% (range 0.1 to 75) with 44% (17 out of 39) of patients having ≥10% of breaths with reverse triggering. With 3 µV threshold, 26% (10 out of 39) of patients had ≥10% reverse triggered breaths. Importantly, patients who resented more reverse triggering were more likely to be on an assisted mode or extubated in the following 24 hours than patients who had low rate of RT (68% vs 35%; p=0.039). We also developed a 3 hours model of reverse triggering in pigs by modifying tidal volume, respiratory rate and level of sedation. Our approach to induce reverse triggering was not only feasible, but consistently reproducible in all animals, although with different presentations in terms of breathing effort and entrainment pattern. The most frequent entrainment pattern observed was 1:1, occurring in 83% of the total animals. Compared to passive ventilation (no breathing effort), RT group had significantly lower tidal volume (7 vs 10 ml/kg) and higher respiratory rate (45 vs 31 bpm) whereas no differences were found in other cardiorespiratory and sedation variables, nor in lung injury indicators after the study period. In order to study the impact of RT on diaphragm injury, we divided the RT group in 3 subgroups based on the level of breathing effort calculated by the pressure time product. Thus, 4 experimental groups were analyzed: Passive (no breathing effort), RT with low effort, RT with middle effort and RT with high effort. Function of the diaphragm was assessed by the ability to generate force, which correspond to the transdiaphragmatic pressure whilst diaphragm structure was evaluated using histological samples and serum troponin I as biomarker of muscle injury. We found that RT affects diaphragm function in two opposite directions. On one hand, animals with RT and low breathing effort showed a significant increase in force of 10% as compared to baseline. On the other hand, animals with RT and high breathing effort showed a larger decrease in force (34%) as compared to baseline. This difference was significantly different with the other experimental groups. Moreover, histologic analysis of diaphragm myofibers showed that RT with high breathing effort had significant lower myofiber cross-sectional area than passive group. Also, when comparing abnormal myofibers between groups, a significantly lower proportion of small fiber size were found in RT whit high breathing effort in comparison to passive group. No differences were found in serum troponin I neither overtime nor between groups. In conclusion, an EAdi-based automated reverse triggering detection showed that this asynchrony is highly prevalent early after intubation under assist-control ventilation; the incidence depends on the magnitude of the activity detected and that reverse triggering seems to occur during the transition phase between deep sedation and the onset of patient triggering. In addition, the creation of a reverse triggering model revealed this phenomenon very complex, with high variability in terms of entrainment pattern and level of breathing effort. Finally, we have confirmed that RT dyssynchrony affects diaphragm function and this effect is modulated by the level of respiratory effort. Reverse triggering with low breathing effort seems to have a protective role on diaphragm function whereas reverse triggering with high breathing effort may favor eccentric myotrauma.Mechanical ventilation (MV) is used to sustain life in patients admitted to the intensive care unit for a wide spectrum of indications such as elective surgical procedures, septic shock, multiple organic failure and acute respiratory distress syndrome. Safe and effective ventilation depends on a smooth interaction between these two independent systems: the patient and the mechanical ventilator. Any mismatch between the patient and mechanical ventilator in terms of breath delivery timing, as well as the inability of the ventilator’s flow delivery to match the patient’s flow demand, is referred to as patient-ventilator dyssynchrony (PVD). Reverse Triggering (RT) is a type of PVD where muscle contractions are delayed, starting a certain amount of time after the machine triggered breath and occurring under different entrainment patterns. RT was originally described in 2013, in sedated patients admitted to the intensive care unit. Unfortunately, data about RT until now is scarce and its relevance remains totally uncertain. If any, the relevance of RT might be attributed to 2 main factors: the frequency of this PVD and its potential consequences in both lung and diaphragm injury. The group of different adverse patient–ventilator interactions leading to diaphragm atrophy and injury and resulting in a final common pathway of diaphragm weakness are denominated myotrauma. Particularly, RT is thought to cause eccentric myotrauma, which is a muscle contraction while muscle is lengthening during the ventilator’s expiratory phase while lung volume is decreasing. Based on animal and human studies, the impact of RT (if any) might be mediated by the level of breathing effort. In this thesis we aimed to describe the incidence of RT in patients early after intubation and admission to the intensive care unit and also to study the impact of RT with different levels of breathing effort on diaphragm injury (function and structure) in an animal model of RT with acute respiratory distress syndrome. To determine RT incidence, we conducted ancillary study in patients with continuous monitorization of the electrical activity of the diaphragm (EAdi). We developed a method for automatic detection of reverse triggering using EAdi and airway pressure curve. We additionally compared patients’ demographics, sedation depth and ventilation settings according to the median rate of reverse triggering, including time to transition to assisted ventilation or extubation. We found that our new automatic method presented a good diagnostic accuracy (98% total accuracy). Using a threshold of 1 µV for EAdi, median reverse triggering rate was 8% (range 0.1 to 75) with 44% (17 out of 39) of patients having ≥10% of breaths with reverse triggering. With 3 µV threshold, 26% (10 out of 39) of patients had ≥10% reverse triggered breaths. Importantly, patients who resented more reverse triggering were more likely to be on an assisted mode or extubated in the following 24 hours than patients who had low rate of RT (68% vs 35%; p=0.039). We also developed a 3 hours model of reverse triggering in pigs by modifying tidal volume, respiratory rate and level of sedation. Our approach to induce reverse triggering was not only feasible, but consistently reproducible in all animals, although with different presentations in terms of breathing effort and entrainment pattern. The most frequent entrainment pattern observed was 1:1, occurring in 83% of the total animals. Compared to passive ventilation (no breathing effort), RT group had significantly lower tidal volume (7 vs 10 ml/kg) and higher respiratory rate (45 vs 31 bpm) whereas no differences were found in other cardiorespiratory and sedation variables, nor in lung injury indicators after the study period. In order to study the impact of RT on diaphragm injury, we divided the RT group in 3 subgroups based on the level of breathing effort calculated by the pressure time product. Thus, 4 experimental groups were analyzed: Passive (no breathing effort), RT with low effort, RT with middle effort and RT with high effort. Function of the diaphragm was assessed by the ability to generate force, which correspond to the transdiaphragmatic pressure whilst diaphragm structure was evaluated using histological samples and serum troponin I as biomarker of muscle injury. We found that RT affects diaphragm function in two opposite directions. On one hand, animals with RT and low breathing effort showed a significant increase in force of 10% as compared to baseline. On the other hand, animals with RT and high breathing effort showed a larger decrease in force (34%) as compared to baseline. This difference was significantly different with the other experimental groups. Moreover, histologic analysis of diaphragm myofibers showed that RT with high breathing effort had significant lower myofiber cross-sectional area than passive group. Also, when comparing abnormal myofibers between groups, a significantly lower proportion of small fiber size were found in RT whit high breathing effort in comparison to passive group. No differences were found in serum troponin I neither overtime nor between groups. In conclusion, an EAdi-based automated reverse triggering detection showed that this asynchrony is highly prevalent early after intubation under assist-control ventilation; the incidence depends on the magnitude of the activity detected and that reverse triggering seems to occur during the transition phase between deep sedation and the onset of patient triggering. In addition, the creation of a reverse triggering model revealed this phenomenon very complex, with high variability in terms of entrainment pattern and level of breathing effort. Finally, we have confirmed that RT dyssynchrony affects diaphragm function and this effect is modulated by the level of respiratory effort. Reverse triggering with low breathing effort seems to have a protective role on diaphragm function whereas reverse triggering with high breathing effort may favor eccentric myotrauma.Mechanical ventilation (MV) is used to sustain life in patients admitted to the intensive care unit for a wide spectrum of indications such as elective surgical procedures, septic shock, multiple organic failure and acute respiratory distress syndrome. Safe and effective ventilation depends on a smooth interaction between these two independent systems: the patient and the mechanical ventilator. Any mismatch between the patient and mechanical ventilator in terms of breath delivery timing, as well as the inability of the ventilator’s flow delivery to match the patient’s flow demand, is referred to as patient-ventilator dyssynchrony (PVD). Reverse Triggering (RT) is a type of PVD where muscle contractions are delayed, starting a certain amount of time after the machine triggered breath and occurring under different entrainment patterns. RT was originally described in 2013, in sedated patients admitted to the intensive care unit. Unfortunately, data about RT until now is scarce and its relevance remains totally uncertain. If any, the relevance of RT might be attributed to 2 main factors: the frequency of this PVD and its potential consequences in both lung and diaphragm injury. The group of different adverse patient–ventilator interactions leading to diaphragm atrophy and injury and resulting in a final common pathway of diaphragm weakness are denominated myotrauma. Particularly, RT is thought to cause eccentric myotrauma, which is a muscle contraction while muscle is lengthening during the ventilator’s expiratory phase while lung volume is decreasing. Based on animal and human studies, the impact of RT (if any) might be mediated by the level of breathing effort. In this thesis we aimed to describe the incidence of RT in patients early after intubation and admission to the intensive care unit and also to study the impact of RT with different levels of breathing effort on diaphragm injury (function and structure) in an animal model of RT with acute respiratory distress syndrome. To determine RT incidence, we conducted ancillary study in patients with continuous monitorization of the electrical activity of the diaphragm (EAdi). We developed a method for automatic detection of reverse triggering using EAdi and airway pressure curve. We additionally compared patients’ demographics, sedation depth and ventilation settings according to the median rate of reverse triggering, including time to transition to assisted ventilation or extubation. We found that our new automatic method presented a good diagnostic accuracy (98% total accuracy). Using a threshold of 1 µV for EAdi, median reverse triggering rate was 8% (range 0.1 to 75) with 44% (17 out of 39) of patients having ≥10% of breaths with reverse triggering. With 3 µV threshold, 26% (10 out of 39) of patients had ≥10% reverse triggered breaths. Importantly, patients who resented more reverse triggering were more likely to be on an assisted mode or extubated in the following 24 hours than patients who had low rate of RT (68% vs 35%; p=0.039). We also developed a 3 hours model of reverse triggering in pigs by modifying tidal volume, respiratory rate and level of sedation. Our approach to induce reverse triggering was not only feasible, but consistently reproducible in all animals, although with different presentations in terms of breathing effort and entrainment pattern. The most frequent entrainment pattern observed was 1:1, occurring in 83% of the total animals. Compared to passive ventilation (no breathing effort), RT group had significantly lower tidal volume (7 vs 10 ml/kg) and higher respiratory rate (45 vs 31 bpm) whereas no differences were found in other cardiorespiratory and sedation variables, nor in lung injury indicators after the study period. In order to study the impact of RT on diaphragm injury, we divided the RT group in 3 subgroups based on the level of breathing effort calculated by the pressure time product. Thus, 4 experimental groups were analyzed: Passive (no breathing effort), RT with low effort, RT with middle effort and RT with high effort. Function of the diaphragm was assessed by the ability to generate force, which correspond to the transdiaphragmatic pressure whilst diaphragm structure was evaluated using histological samples and serum troponin I as biomarker of muscle injury. We found that RT affects diaphragm function in two opposite directions. On one hand, animals with RT and low breathing effort showed a significant increase in force of 10% as compared to baseline. On the other hand, animals with RT and high breathing effort showed a larger decrease in force (34%) as compared to baseline. This difference was significantly different with the other experimental groups. Moreover, histologic analysis of diaphragm myofibers showed that RT with high breathing effort had significant lower myofiber cross-sectional area than passive group. Also, when comparing abnormal myofibers between groups, a significantly lower proportion of small fiber size were found in RT whit high breathing effort in comparison to passive group. No differences were found in serum troponin I neither overtime nor between groups. In conclusion, an EAdi-based automated reverse triggering detection showed that this asynchrony is highly prevalent early after intubation under assist-control ventilation; the incidence depends on the magnitude of the activity detected and that reverse triggering seems to occur during the transition phase between deep sedation and the onset of patient triggering. In addition, the creation of a reverse triggering model revealed this phenomenon very complex, with high variability in terms of entrainment pattern and level of breathing effort. Finally, we have confirmed that RT dyssynchrony affects diaphragm function and this effect is modulated by the level of respiratory effort. Reverse triggering with low breathing effort seems to have a protective role on diaphragm function whereas reverse triggering with high breathing effort may favor eccentric myotrauma.