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Early passive orthostatic training prevents diaphragm atrophy and dysfunction in intensive care unit patients on mechanical ventilation: A retrospective case‒control study
This is the first study using diaphragmatic ultrasound to evaluate the efficacy of early passive orthostatic training.
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Early passive orthostatic training added to physiotherapy can ameliorate diaphragm dysfunction of critical patients with mechanical ventilation.
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Outcome measures included the assessment of diaphragmatic thickness, diaphragm contractile fraction, theparameters of ventilatory and laboratory data.
Abstract
Background
Intensive care unit (ICU) patients on mechanical ventilation (MV), who are always bedridden, easily develop diaphragm atrophy and dysfunction. However, few studies have assessed diaphragmatic thickness and functional changes after early passive orthostatic training.
Objectives
This is the first study to investigate the efficacy of early passive orthostatic training in preventing diaphragm atrophy and dysfunction in ICU patients on MV.
Methods
In this randomized retrospective case‒control study, 81 ICU patients on MV for 8 days or longer were enrolled. Forty-four patients received early passive orthostatic training initiated within 72 h of MV initiation (training group), and 37 patients did not receive training (no-training group). The protocol was performed for seven days, once a day for 30 min. The primary outcomes were diaphragmatic thickness and diaphragm contractile fraction (TFdi). The ventilatory parameters were secondary outcomes.
Results
This study included 81 (45 male) ICU patients on MV [(mean ± SD) age = (60.63 ± 7.88) years]. The training group had a larger diaphragmatic thickness at end-expiration (Tdi,ee) and a smaller magnitude of decrease in Tdi,ee and TFdi (p = 0.001, 0.029, and <0.001, respectively) than the no-training group after 7 days of training. The mean arterial pressure, fraction of inspired oxygen, and white blood cell levels were decreased in the training group compared with the no-training group (p = 0.003, 0.001, and 0.026, respectively), but lactic acid levels decreased slightly in the training group with no significant difference (p = 0.708).
Conclusions
Early passive orthostatic training is suitable to ameliorate diaphragm atrophy and dysfunction in ICU patients on MV.
Intensive care unit (ICU) patients with a life-threatening disease are subsequently bedridden with prolonged immobilization to maintain medical stability.
Mechanical ventilation (MV) is one of the most important life-supporting interventions to help ICU patients survive, with up to 40% of patients requiring MV.
However, during the acute stage, prolonged physical inactivity and being bedridden due to MV negatively affect the neuromuscular and respiratory systems of most patients, leading to adverse unintended outcomes, such as muscle atrophy, restricted joint mobility,
These adverse outcomes result in more time being needed to wean patients from the ventilator and increases morbidity, mortality, and healthcare expenditures.
Coexistence and impact of limb muscle and diaphragm weakness at time of liberation from mechanical ventilation in medical intensive care unit patients.
Diaphragmatic weakness is regarded to be a multistep process that is not only induced by ventilator-caused diaphragm disuse but also involves several other risk factors, such as sepsis
Most tools for assessing diaphragm thickness and function during the respiratory cycle require patient cooperation and lack specificity. Compared to the technically difficult methods used for measuring transdiaphragmatic pressure,
However, patients hospitalized in the ICU commonly have low consciousness or severe paralysis, which prevents them from standing safely or transferring independently.
which can help patients passively stand upright at various horizontal angles without considerable support. Additionally, this method may optimize oxygenation by improving ventilation and ventilation-perfusion matching.
Physiotherapy for adult patients with critical illness: recommendations of the European respiratory society and European society of intensive care medicine task force on physiotherapy for critically ill patients.
reported that for patients ventilated for more than five days who received passive standing for five minutes from a horizontal position to 70°, their minute and tidal ventilation increased significantly, but only temporarily. Furthermore, these ventilatory changes and the increase in maximum inspiratory pressure and functional residual capacity also occurred in healthy subjects who received passive standing.
The diaphragm plays a primary role in the respiratory cycle. Studies have proven that the change in diaphragm thickness between at-end-expiration and at-end-inspiration was positively correlated with maximum inspiratory pressure, peak inspiratory flow, and vital capacity.
Accordingly, we propose that early passive orthostatic training with a tilt table is a valid intervention method to prevent diaphragm atrophy and dysfunction in MV patients. In previous studies, the effect of passive orthostatic training on the respiratory muscle was assessed by pulmonary function.
This is the first study in which diaphragmatic ultrasound was used to examine the effect of early passive orthostatic training with a tilt table on diaphragm structure and function in Chinese Han ICU patients on MV.
Methods
Study design
This was a single-center, randomized retrospective case‒control study conducted from January 1, 2020, to September 30, 2021, in an ICU in northern China. The study protocol complied with the Declaration of Helsinki, which was approved by the Ethics Committee of our institution, and all the participants’ kin gave written informed consent for passive orthostatic training.
Participants
Eligible patients were identified by inspecting their ICU medical records. Patients were eligible for enrollment if they had received MV for more than 8 days and had complete end-expiratory and end-inspiratory diaphragmatic thickness data. According to whether they received early passive orthostatic training for 7 days, the patients were divided into a training group (TG; 44 patients) and a no-training group (NG; 37 patients) (Fig. 1). Patients’ baseline information, including sex, age, body mass index (BMI), Acute Physiology and Chronic Health Evaluation II (APACHE II) score, and clinical variables, were recorded in their ICU medical records before (Day 0) and after 7 days of early passive orthostatic training (Day 8). Diaphragmatic ultrasound was used to evaluate diaphragm thickness and function at Day 0 and Day 8.
Early passive orthostatic training was initiated in patients with stable hemodynamic and respiratory conditions within 72 h of MV initiation. First, the mean airway pressure, fraction of inspired oxygen (FiO2) and time of measurement were recorded, followed by vital signs to assure hemodynamic stability. Subsequently, end-expiratory and end-inspiratory diaphragm thicknesses were measured. Once all variables were assessed, early passive orthostatic training was conducted by experienced ICU physical therapists, usually starting at 9 am. Each patient in the TG was positioned on an electrical tilt table. Strips were fixed to the patient's chest, hips and knees, and their feet were strapped to two footplates. The tilt table was continuously adjusted from 0° to 90°, according to the patient's clinical status (physiotherapists made adjustments for patients based on physical therapists’ clinical judgment). Training sessions lasted for 30 min based on the daily protocol. The first 15 min was used to improve the tilt and stabilization at each level, and the last tilt (the highest) of each day lasted for 15 min.
During the verticalization procedure, the patient's mean arterial pressure, heart rate, and pulse blood oxygen saturation were monitored. Rehabilitation therapy was interrupted when the following criteria were met: the presence of syncope or presyncope symptoms, such as tachypnoea, a new arrhythmia, pallor, or increased sweating. The interruption criteria can be found elsewhere.
Comparison of orthostatic reactions of patients still unconscious within the first three months of brain injury on a tilt table with and without integrated stepping. A prospective, randomized crossover pilot trial.
After an interruption, patients were allowed to be verticalized further. However, this was not a requirement for subjects during the study protocol.
Measurements
Diaphragm thickness and diaphragm thickening fraction were assessed by ultrasound. All participants underwent a B-mode ultrasound examination using a portable bedside ultrasound machine with a high frequency (13 MHz) linear array transducer based on a previously described method.
With the patient in the semirecumbent position, the probe was perpendicularly placed to the right chest wall at the zone of apposition between the ninth or tenth right intercostal space in the anterior or midaxillary lines,
and the diaphragm was identified as the middle hypoechoic layer structure surrounded by two hyperechoic lines (representing the diaphragmatic pleura and the peritoneal membranes). The thickness of the right diaphragm was assessed using electronic calipers at end-expiration (Tdi,ee) and end-inspiration (Tdi,ei, maximal diaphragm thickness during inspiration) separately by time-motion mode (M-mode). Tdi,ee and Tdi,ei were defined as the distance between the internal border of the pleura and peritoneal membranes. Diaphragm contractile activity was quantified as TFdi, computed as (Tdi,ei -Tdi,ee)/Tdi,ee. This index has been validated and used to monitor diaphragm contractile activity and respiratory work of breathing in MV patients.
All measurements were conducted during three uninterrupted and undisturbed breath cycles by the same experienced examiner, and the calculated average of the individual values was recorded. Assessments were carried out in the same identified area, and the depth settings were constant for each patient, except for rare cases in which a slightly deeper setting was required due to the presence of a significant amount of subcutaneous edema.
Statistical analysis
All data were analyzed using SPSS ver. 22.0 MacIntosh. The Shapiro‒Wilk normality test was used to check the normality distribution of all data. Continuous variables are presented as the mean ± SD if they conformed to a normal distribution; otherwise, they are presented as the median (interquartile range). Categorical variables are presented as numbers (percentages). Parametric tests (the independent t-test, the paired t-test) and nonparametric tests (the Mann‒Whitney U test) were used to compare the differences between these variables. The paired t-test was used to compare the Tdi,ee, Tdi,ei, and TFdi at different times in each group. The independent t-test was used to test the difference between the TG and NG. The Mann‒Whitney U test was used to compare continuous data between the two groups. Two-tailed p values less than 0.05 were considered significant.
Results
Participants
A total of 81 (45 males) MV patients aged 60.63 years (7.88) who met the inclusion criteria during ICU admission were included in this study. Forty-four patients were in the TG, and thirty-seven patients were in the NG. Table 1 outlines the baseline characteristics of the two groups. There were no significant differences in age, sex, BMI, or APACHE II scores between the patients in these two groups (p > 0.05). Males accounted for more than half of the patients. There were no differences in the mean airway pressure, FiO2, lactic acid levels, or white blood cell levels (p > 0.05) between the two groups. FiO2 was set and constantly adjusted by the clinical physician during hospitalization (according to clinical empirical treatment standards). All patients tolerated the study protocol well, with no signs of respiratory distress or overassistance. All patients were alive and well at discharge.
Table 1Baseline characteristics of the enrolled patients in the two groups.
Diaphragmatic thickness and diaphragm contractile fraction after MV
For patients in the TG, early passive orthostatic training was provided within 72 h of MV initiation and conducted for 7 days; for patients in the NG, medical and nursing treatment was provided in the supine position. Measurements of diaphragm thickness and the calculation of TFdi were completed successfully at the end of exhalation (Tdi,ee) and inhalation (Tdi,ei) using ultrasound for all patients at Day 0 and Day 8 (Fig. 2). The average Tdi,ee, Tdi,ei, and TFdi were significantly decreased in all patients at Day 8 compared to Day 0 (p < 0.001, <0.001, and <0.001, respectively) (Table 2).
Fig. 2Example of ultrasound imaging before and after early passive orthostatic training. a Left, Tdi,ei and Tdi,ee were viewed at the apposition of A and B, respectively; Right, diaphragm was viewed in B-mode before training. b Left, Tdi,ei and Tdi,ee were viewed at the apposition of A and B, respectively; Right, the diaphragm was viewed in B-mode after training. Tdi,ei end-inspiratory thickness, Tdi,ee end-expiratory thickness.
Changes in Tdi,ee, Tdi,ei, and TFdi after 7 days of training
Before early passive orthostatic training (at Day 0), no significant differences were observed in Tdi,ee, Tdi,ei, and TFdi (p = 0.313, 0.317, and 0.579, respectively) between the TG and NG (Table 3). After 7 days of training, the average Tdi,ee and Tdi,ei were larger in the TG than in the NG, and the difference was marginally significant (p = 0.090 and 0.055, respectively); however, TFdi was significantly larger in the TG than in the NG (p = 0.001) (Table 4). Furthermore, we found that the magnitude of the decrease in Tdi,ee and TFdi before and after 7 days of training was obviously smaller in the TG than in the NG (8% vs. 11%, p = 0.029; 10% vs. 16%, p < 0.001, respectively) (Fig. 3).
Table 3Comparison of TD and TFdi values in the two groups at Day 0.
Fig. 3Comparison of the magnitude of the decrease in Tdi,ee and TFdi between the no-training group and training group (after 7 days of training). a: the magnitude of the decrease in Tdi,ee between the two groups, b: the magnitude of the decrease in TFdi between the two groups.
After early passive orthostatic training, the ventilator monitoring data reflected that the mean airway pressure and FiO2 were significantly decreased in the TG compared to the NG (p = 0.003 and 0.001, respectively). Laboratory results showed that the white blood cell levels were lower in the TG than in the NG (p = 0.026), and the lactic acid levels had decreased in the TG, with no significant differences between the two groups (p = 0.708) (Table 5).
Table 5Comparative analysis of the ventilation parameters and laboratory data of the two groups at Day 8.
To date, the multiple advantages of early passive orthostatic training have not been quantitatively reported, although passive orthostatic training has been determined to be an early rehabilitation project in ICUs.
This is the first study using diaphragmatic ultrasound to investigate whether early passive orthostatic training with a tilt table may prevent diaphragm atrophy and dysfunction in Chinese Han ICU patients on MV. The main findings in this study were that patients who received the intervention training experienced a smaller decrease in Tdi,ee, while similarly ventilated patients who did not receive the intervention experienced a greater decrease (8% vs. 11%). A similar effect was observed in TFdi (10% vs. 16%). We also found that early passive orthostatic training can improve clinical results related to respiratory function and decrease the level of inflammation. Based on the current findings, we conclude that providing early passive orthostatic training for ICU patients on MV could be feasible and beneficial.
Several studies have reported that approximately 80% of MV patients exhibit diaphragm weakness.
Coexistence and impact of limb muscle and diaphragm weakness at time of liberation from mechanical ventilation in medical intensive care unit patients.
This study further demonstrated different degrees of diaphragm atrophy and dysfunction caused by MV over time. Both clinical and animal studies have demonstrated that increased oxidative stress, acute disuse atrophy,
myofibril damage, and contractile dysfunction, as well as the activation of several major proteolytic pathways (ubiquitin‒proteasome, caspases, calpains) caused by diaphragmatic inactivity with controlled MV,
contribute to reductions in diaphragmatic force. Recently, published human data also showed that the lysosome-mediated autophagy pathway is significantly upregulated in the diaphragm during MV.
Measurement of twitch transdiaphragmatic, esophageal, and endotracheal tube pressure with bilateral anterolateral magnetic phrenic nerve stimulation in patients in the intensive care unit.
Studies have shown that diaphragmatic ultrasound is the most feasible, accurate, and convenient method for measuring diaphragm structure (i.e., thickness) and function (i.e., contractility) in daily clinical practice,
especially in the face of low cooperation of ICU patients and the shortage of human resources of critical care teams. Our data were collected by an experienced clinician who provided reproducible results to maintain high inter- and intraexaminer consistency.
reported that using ultrasound to assess the right hemidiaphragm was more feasible and provided better visualization than assessing the left hemidiaphragm, which can help track a patient's status on MV. Roussos et al.
found that the thickness of the right hemidiaphragm is also correlated with the extent of muscle contractile activation during MV. Hence, we collected data from the right hemidiaphragm to assess diaphragm structure and function in patients.
In this study, we found that early passive orthostatic training attenuated the decline rate of Tdi,ee and TFdi caused by MV, which could be explained by the following effects. As participants move from the supine to the upright position, gravitational forces displace the diaphragm and abdominal contents to a more descended position,
so physiological adaptation is transferred from the abdominal and diaphragm muscles to the force. First, a reflex augmentation of the phrenic activation occurs to compensate for the reduced mechanical effectiveness on inspiratory effort caused by the shortening and flattening
of the diaphragm muscle, which is indicated by a virtually unchanging transdiaphragmatic pressure accompanying a nearly fivefold increase in diaphragm electrical activity. Second, adaptation to the gravitational displacement of the abdominal contents reduces abdominal compliance and increases intra-abdominal pressure, which further increases diaphragm contractility to overcome intra-abdominal pressure to preserve transdiaphragmatic pressure.
The role of abdominal compliance, the neglected parameter in critically ill patients - a consensus review of 16. Part 2: measurement techniques and management recommendations.
Simultaneously, in both MV patients and healthy control subjects, there is a strong relationship between the contractile activity level and diaphragm thickness.
Furthermore, because early orthostatic training is passive, this technique can be used in patients who cannot participate in active diaphragmatic exercises due to the impaired ability to cooperate (i.e., ICU patients with neurological injuries) and can also be used in conjunction with other techniques (i.e., diaphragmatic nerve stimulation) to further improve diaphragmatic structure and function in debilitated patients.
Our study also revealed that early passive orthostatic training could improve clinical outcomes related to respiratory function. In previous studies, respiratory therapists used a tilt table for critical patients, and their cardiopulmonary function improved either during or immediately after the intervention.
In the present study, there were significant declines in the mean airway pressure and FiO2. These results indicated that the training group achieved better oxygenation
Effect of regulating airway pressure on intrathoracic pressure and vital organ perfusion pressure during cardiopulmonary resuscitation: a non-randomized interventional cross-over study.
which suggested that passive tilt table training was suitable for the patients’ physiology and tended to decrease the mean airway pressure, simultaneously reducing the risk of lung injury caused by mechanical ventilation.
Regarding white blood cell levels, there was a significant decrease in the TG compared to the NG. Because critical MV patients generally have low immunity and nutritional function and are bedridden for prolonged periods, they are prone to infection.
Numerous basic science animal experiments have provided additional evidence for a causal relationship between infection and diaphragmatic weakness, showing that infections severely reduce diaphragm strength by up to 80% within 24 h.
Our results suggest that early passive orthostatic training may serve as an indirect intervention method to reduce inflammation and further prevent diaphragm atrophy.
Alternatively, we observed a slight, nonsignificant decrease in lactic acid levels. Lactic acid is a sensitive indicator of tissue hypoxia
first found that the activity of muscle fibers decreased under high lactic acid conditions and modulated the attenuated increase in lactic acid by inspiratory muscle training. Hence, whether passive standing with a tilt table can effectively reduce lactic acid levels cannot be determined through this preliminary study.
Study limitations
Several limitations of this study should be mentioned. First, this study had a single-center design. Passive orthostatic training significantly prevented diaphragm atrophy in Chinese Han patients receiving MV for more than 8 days; however, the effect of passive orthostatic training on a larger, multiethnic sample population of patients with any complications should be studied due to the relatively high degree of variation in diaphragm function in MV patients reported in the previous literature.
Unfortunately, the sample size of the study was limited because of geographical restrictions, and it is difficult to identify some significant differences if we divide these patients into groups according to their complications. Second, passive orthostatic training was performed seven times, once a day for 30 min. Studies on variations in the frequency and magnitude that are appropriate for MV patients may be required to optimize and maintain the benefit. Unfortunately, this was a retrospective study, and the sample size was too small to validate the results. Third, due to nonstandard ventilator settings, the effects of different mechanical ventilation modes cannot be determined, and some differences may exist between the groups. However, all patients received the same routine clinical intensive care for nutrition, sedation, or changes in ventilatory support; thus, we considered that there were no significant differences between the two groups. Finally, in the present study, the long-term outcomes (i.e., the time of ventilator weaning, the length of ICU stay, or quality of life) of early passive orthostatic training were not investigated, which may prevent the assessment of whether the outcomes are sustained, and we plan to recruit more patients for further research. Despite these limitations, this study adds value to early passive orthostatic training in Chinese Han ICU patients on MV.
Conclusions
Our study demonstrates that early passive orthostatic training with a tilt table is safe and effective in preventing decreases in Tdi,ee and TFdi and improving the partial clinical index correlated with respiratory function in Chinese Han ICU patients on MV. Diaphragmatic ultrasound is a useful and convenient technique to monitor diaphragm structure and function in critical MV patients. Early passive orthostatic training with a tilt table may provide a future option for preventing diaphragm atrophy in critical MV patients whenever possible. Further study is needed to validate the impact of early passive orthostatic training on important clinical outcomes, such as the timing of MV and extubation and the length of ICU stay. Additionally, future studies could be performed to assess the exact effects of early passive orthostatic training on diaphragm structure and function in ICU patients with different diseases.
Sources of financial support
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Conflict of interest statement
We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in the manuscript.
Coexistence and impact of limb muscle and diaphragm weakness at time of liberation from mechanical ventilation in medical intensive care unit patients.
Physiotherapy for adult patients with critical illness: recommendations of the European respiratory society and European society of intensive care medicine task force on physiotherapy for critically ill patients.
Comparison of orthostatic reactions of patients still unconscious within the first three months of brain injury on a tilt table with and without integrated stepping. A prospective, randomized crossover pilot trial.
Measurement of twitch transdiaphragmatic, esophageal, and endotracheal tube pressure with bilateral anterolateral magnetic phrenic nerve stimulation in patients in the intensive care unit.
The role of abdominal compliance, the neglected parameter in critically ill patients - a consensus review of 16. Part 2: measurement techniques and management recommendations.
Effect of regulating airway pressure on intrathoracic pressure and vital organ perfusion pressure during cardiopulmonary resuscitation: a non-randomized interventional cross-over study.
Estimated by independent t tests.
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