Effects of Different Ventilator Settings on Sleep and Inspiratory Effort in Patients with Neuromuscular Disease
http://www.100md.com
美国呼吸和危急护理医学 2005年第9期
Pulmonary Division, Istituto Scientifico di Montescano and Pavia, Fondazione S. Maugeri, IRCCS
Department of Clinical Neurology and Child Psychiatry, IRCCS C. Mondino, Pavia, Italy
ABSTRACT
Patients with neuromuscular disease (NMD) who require long-term ventilation normally have the ventilation set using empirical daytime parameters. We evaluated arterial blood gases (ABG), breathing pattern, respiratory muscle function, and sleep architecture during ventilation with two noninvasive Pressure Support Ventilation (nPSV) settings in nine patients with NMD. The two settings were randomly applied: the usual (US), with the nPSV setting titrated on simple clinical parameters, and the physiological (PHYS), tailored to the patient's respiratory effort. During wakefulness, nPSV significantly improved ABG and minute ventilation and reduced the diaphragmatic pressure-time product (PTPdi/breath), independently of the type of setting (PTPdi/breath spontaneous breathing 5.7 ± 2.4, US 3.2 ± 2, PHYS 3.6 ± 1.6 cm H2O · seconds-1, p < 0.001). However, during sleep, PHY nPSV resulted in a significant improvement of gas exchange, sleep efficiency (71.7% ± 14 US vs. 80.6% ± 8.3 PHYS, p < 0.01) and % of REM sleep (9.1% ± 7 US vs. 17.3% ± 5.4 PHYS, p < 0.01). This improvement was significantly correlated with the reduction in ineffective efforts. In NMD, nPSV is effective in improving daytime ABG and in unloading inspiratory muscles independently of whether it is set on the basis of the patient's comfort or the patient's respiratory mechanics. However, PHYS was associated with better sleep architecture and nighttime gas exchange.
Key Words: noninvasive mechanical ventilation; sleep; polysomnography; respiratory failure; home care
Noninvasive mechanical ventilation (NIMV) is being increasingly used as a treatment for chronic hypercapnic respiratory failure. Its use in patients affected by restrictive thoracic disorders, and in particular in patients with neuromuscular disease, suggested that it alleviates symptoms of chronic hypoventilation in the short term and, according to two small studies, may prolong survival (1eC5). Indeed, a recent Cochrane review stated that "long-term mechanical ventilation should be offered as a therapeutic option to patients with chronic hypercapnic respiratory failure due to neuromuscular diseases" (6). Daytime hypercapnia worsens during sleep, so that the major goal to achieve with the ventilatory treatment, in patients with neuromuscular disease, is the correction of nocturnal hypoventilation (6eC9). When the decision to initiate long-term NIMV is made, the ventilatory parameters to use during the nighttime are mainly determined empirically, based on patient's tolerance when awake and diurnal arterial blood gas variations. No study has so far investigated the possible influence of different ventilator settings, decided a priori according to daytime parameters, on sleep architecture and gas exchange. Indeed, in awake patients with COPD, the empirical setting was shown to parallel, at least to a certain extent, the respiratory muscle unloading and gas exchange achieved when the ventilator was physiologically titrated (10), but was also associated with a significantly higher prevalence of ineffective efforts (i.e., patients' inspiratory efforts unable to trigger the ventilator). In patients with severe respiratory muscle weakness, patienteCventilator dyssynchrony may be a cause of suboptimal ventilation, especially during the nighttime, when profound modifications in the recruitment of the respiratory muscle may occur during the various stages of sleep. The aim of this study was to compare the effects of two ventilation settings on sleep architecture and patienteCventilator interaction in patients already established on long-term mechanical ventilation for neuromuscular disorders. The ventilation settings were the "usual" (US) clinically determined setting and a "physiological" (PHYS) setting based on the recordings of inspiratory muscle effort. Some of the results of this study have been previously reported in the form of an abstract (11).
METHODS
Patients
We studied nine inpatients affected by chronic respiratory failure or nocturnal hypoventilation due to miscellaneous neuromuscular disorders who were admitted during a period of clinical stability for a follow-up control. All of the patients were already established on long-term NIMV. The local Ethics Committee approved the study and the patients gave written formal consent.
Home Mechanical Ventilation
Home noninvasive pressure support ventilation (nPSV) was provided by a portable ventilator and delivered through a nasal mask, except in one patient in whom a full-face mask was alternated with nasal pillows (see online supplement for details). The nPSV had been set at the maximal tolerated inspiratory pressure support able to reduce the awake PaCO2 by more than 5% of that recorded during spontaneous breathing (SB). A preset level of external positive end-expiratory airway pressure (PEEPe) was added. After setting the inspiratory pressure, the level of PEEPe was progressively increased in each patient, according to his or her tolerance.
Measurements
We measured static and dynamic lung volumes, arterial blood gases, and the respiratory pattern. Respiratory mechanics and the respiratory muscles function were assessed using standardized techniques described in detail in the online supplement (12eC15). Respiratory mechanics were assessed using Mead and Wittenberger's technique (12). Inspiratory pulmonary resistance (RL) and elastance (EL) were calculated by fitting the equation of motion of a single-compartment model using multilinear regression. Dynamic positive end-expiratory pressure (PEEPidyn) was obtained from the transdiaphragmatic pressure (Pdi) signal, as the value of Pdi at the moment of zero flow (13).
Daytime Measurements
In the morning of Day 1, patients were asked to breathe spontaneously through the pneumotachograph and were then randomized for 30 minutes of nPSV administered using the following two settings, already described in detail a previous study (10), separated by 20 minutes of unsupported breathing. This period was long enough to bring all the physiologic variables measured back to baseline values.
US. This is the setting described for home mechanical ventilation.
PHYS. This setting provides an inspiratory aid sufficient to reduce the Pdi tidal swing by more than 40% and less than 80% and/or to avoid any positive deflection in Pes during expiration. PEEPe was set at approximately 80% of the PEEPidyn recorded during spontaneous breathing.
All physiologic signals were recorded in the last 5 minutes of each unassisted or assisted breathing period.
This trial was performed using a home care ventilator that allowed us to set the PEEPe at zero (Helia; Saime, Savigny-le Temple, France). All signals were collected using a personal computer equipped with an A/D board, and stored at a sampling rate of 100 Hz.
Arterial blood was sampled from the radial artery at the end of the initial unassisted breathing period and at the end of each period of NIMV with the different settings.
Nighttime Measurements
On two consecutive nights after Day 1, each patient underwent, in random order, two different sleep studies during nPSV using US or PHYS settings.
Full standard night polysomnography (Sleep Lab 1000e; Jaeger, Hochberg, Germany) was performed using standard procedures and scored manually according to Rechtschaffen and Kales' criteria (16). Arousals were scored according to the criteria of the American Sleep Disorders Association (17). All the patients were acclimatized before to the sleep study setting, because they had performed a baseline sleep study before the enrollment in the home NIMV program.
Statistical Analysis
Results are presented as mean and SD. Variations in physiologic indices between spontaneous breathing, US, and PHYS were analyzed using MANOVA analysis; post hoc comparison was made to assess differences within treatments. A p value < 0.05 was chosen as the threshold of statistical significance for this test. The relationships between the variables were evaluated by Pearson's product-moment correlation coefficient. All the analyses were performed using the STATISTICA/W statistical package (Tulsa, OK), and a p value < 0.05 was considered statistically significant.
RESULTS
All the patients tolerated the procedure and completed the study. The patients' characteristics at the time of study, arterial blood gases at enrollment in the home mechanical ventilation program, and the total duration of the program are shown in Table 1.
Daytime Studies
Individual differences in inspiratory and expiratory pressures between US and PHYS are shown in Figures 1A and 1B, and in Table E1 in the online supplement. No significant difference was observed for the inspiratory pressure during US and PHYS. In contrast, a statistically significant difference was found between the mean PEEPe during US and PEEPe during PHYS (Table E1). In comparison with the US, the PHYS resulted in a higher inspiratory pressure in three patients (33.3%) and PEEPe was reduced in three patients.
Table 2 reports data on the respiratory pattern, arterial blood gas concentrations, and respiratory mechanics recorded during spontaneous breathing and during both US and PHYS mechanical ventilation. nPSV significantly improved minute ventilation by increasing tidal volume and reducing the respiratory rate, and likewise significantly improved both PaO2 and PaCO2, independently of the settings used. Finally, the two settings of ventilation considered did not produce statistically different daytime patterns of breathing, blood gases, or respiratory mechanics.
Table 2 also illustrates the mean values of diaphragm function and PEEPidyn recorded in the three experimental conditions. Compared with SB, both ventilator settings induced significant reductions in all the variables of diaphragm effort, as assessed by Pditidal, PTPdi/min, PTPdi/b, and PTPdi/VT.
During ventilation administered with the US, we observed variable degree of Pdi reduction, but one patient had a higher Pditidal during nPSV than during SB. Interestingly, this patient was ventilated with a PEEPe of 4 cm H2O, in the absence of any PEEPidyn during SB (Figure 2).
All patients but three were ventilated during US with a PEEPe higher than the PEEPidyn. The PHYS significantly reduced the amount of PEEPidyn.
While awake, two patients ventilated with the US and one with the PHYS showed ineffective efforts; this difference between treatments was not significant. The prevalence of these efforts in the total respiratory cycles was negligible with both ventilatory settings (8% and 11% with US and PHYS, respectively).
Nighttime Studies
Table 3 reports polysomnographic data obtained during US and PHYS nocturnal ventilation. The sleep study performed during US ventilation showed reduced sleep efficiency and percentage of REM sleep; furthermore, two patients did not have REM sleep. Nocturnal gas exchange was significantly impaired, as demonstrated by the sleep time spent with SaO2 less than 90% and the desaturation index. PHYS ventilation significantly improved sleep quality by increasing sleep efficiency and the amount of REM sleep, reducing the arousal index and improving gas exchange; furthermore, REM sleep was recorded in all patients.
During sleep with US ventilation, all but two patients showed ineffective efforts during non-REM (NREM) sleep (range 36eC240 events/hour). As shown in Table 3, during PHYS ventilation we observed a statistically significant lower number of ineffective efforts index during NREM sleep as compared with US ventilation; ineffective efforts were completely eliminated in three patients during PHYS ventilation. When we excluded these three patients from the analysis, the remaining six patients still had a statistically significant reduction of ineffective-effort index from 91.7 ± 98 to 31.7 ± 19.6 (p < 0.05). In all patients, the improvement of sleep quality, expressed by increased REM sleep (% of total sleep time), was strongly correlated to the reduction of ineffective efforts (r = eC0.82, p = 0.02; Figure 3).
During US ventilation, three patients had episodes of central apnea (central apnea index /> 5 events/hour; range, 5eC33 events/hour), associated with episode of oxygen desaturation, whereas during PHYS ventilation only one patient showed persistence of central apnea (6.3 events/hour). Both during US and PHYS ventilation a negative correlation was found between central apnea index and amount of REM sleep (expressed as % of total sleep time) (r = eC0.79, p < 0.05; r = eC0.83, p < 0.05, respectively). It is worth noting that the PHYS lowered the nPSV value in patients with central apneas: the difference in nPSV between patients ventilated with the PHYS and US, although not statistically significant, was eC2.25 ± 2.9 cm H2O in patients with central apneas and 0.5 ± 4 cm H2O in those without central apneas during US ventilation.
DISCUSSION
This study shows that, in stable patients with neuromuscular disorders, the settings of NIMV chosen on an empirical basis while the patient is awake do not predict ventilator synchrony while asleep, and that an incorrect titration of inspiratory support or PEEPe may impede the trigger of the mechanical breath. A physiological setting, based on recording the inspiratory efforts, may minimize the rate of ineffective efforts, resulting in improvement of sleep quality and gas exchange. During wakefulness, both settings are effective in improving arterial blood gases and in unloading inspiratory muscles.
Our results therefore suggest that when a patient with nocturnal hypoventilation enters a home ventilation program, the efficacy of the nPSV should be tested by polysomnography to verify the effect of the settings defined during daytime.
Daytime Studies
US settings of NIMV resulted in all but one patient (89%) having a level of inspiratory assistance sufficient to reduce the Pdi by more than 40% of that recorded during SB; this "success rate" is higher than that recorded in patients with COPD (65%) (10).
In patients with neuromuscular disorders, the titration of PEEPe seems to be more critical than that of the inspiratory pressure, because these patients may have either a negligible levels of PEEPidyn (< 1 cm H2O) or values higher than 2 cm H2O, which may be considered the limit for applying PEEPe in an attempt to minimize the inspiratory load due the presence of PEEPidyn (18). Considering the severe weakness of these patients' respiratory muscles, the lack of compensation of this resistive threshold may contribute to worsening the load/capacity balance per breath (i.e., the amount of Pdi generated per single breath, compared with the maximal Pdi) and, on the other hand, decrease the trigger sensitivity. In this respect, three of our patients had ineffective efforts while awake.
Conversely, the titration of PEEPe is also critical in patients not showing any PEEPidyn. Most of the so-called "bilevel" ventilators designed specifically for home NIMV are provided with a continuous air flow, so that a positive pressure of 2 cm H2O is delivered continuously, including during the expiratory phase. The application of this minimal PEEPe in the absence of dynamic hyperinflation may be followed by recruitment of the expiratory muscles (19), as illustrated for a representative patient in Figure 2.
Nighttime Studies
Sleep might worsen respiratory function in patients with chronic neuromuscular disorders. Sleep architecture may be altered with a high percentage of sleep in stage 1 and 2, a low percentage of slow wave sleep and/or REM sleep (20), and a high number of arousals related to oxygen desaturation episodes (21).
The effect of NIMV on sleep quality is varied because, although sleep appeared to be improved in different studies, it rarely became normal (4, 21eC26). The ventilator setting seems to be crucial to improve sleep quality and gas exchange. In fact, in this study we found that two different problems arose during nocturnal mechanical ventilation: a large number of ineffective breathing efforts in several patients and the occurrence of episodes of central apnea.
The improvement of sleep quality during PHYS setting was demonstrated by an increased amount of REM sleep and reduced number of arousals. The increasing percentage of REM sleep observed during PHYS ventilation was correlated with the reduction in ineffective efforts.
A phenomenon of missing or ineffective efforts (i.e., Pdi swings unable to trigger the ventilator) has been shown to occur quite often in ventilator-dependent patients with COPD (15). High resistance to airflow, PEEPidyn, low elastic recoil, high ventilatory demands, and short expiratory time on the ventilator has been advocated to explain this phenomenon in mechanically ventilated patients. We found that, when awake, patients with neuromuscular disease had a negligible amount of patienteCventilator mismatching, probably due to the different mechanical properties. However, this scenario changed considerably during sleep, when the prevalence of ineffective efforts became higher, particular when the patients were receiving ventilation set according to the usual clinical parameters. The PHYS settings resulted in a complete disappearance of the dyssinchrony in three patients and in a significant reduction in the remaining ones. This phenomenon has not been previously described, perhaps because of the different type of ventilation used in the past. The type of mechanical ventilation generally chosen in previous studies was the assist-control mode (22, 23, 27, 28) or a pressure control with a back-up respiratory rate so that the patients' respiratory rate during sleep was the same as the back-up rate of the ventilator (29). In our study, patients received bilevel ventilation in a spontaneous mode so that spontaneous respiratory activity was needed to maintain adequate minute ventilation. The potential benefit of timed versus spontaneous modes of ventilation have not been ever assessed in details, as stated by the Consensus Conference on Clinical Indications for Noninvasive Positive Pressure Ventilation in Chronic Respiratory Failure Due to Restrictive Lung Disease, COPD, and Nocturnal Hypoventilation (30).
Factors that could contribute to onset of ineffective efforts may differ from patient to patient: reduction in respiratory drive, reduction in respiratory muscle strength, increased inspiratory load due to augmented upper airway resistance, and mouth leaks may all contribute to the inability to trigger the ventilator adequately (7, 24, 31). In particular, the reduced amount of PEEPidyn with PHY settings may have contributed to improving the trigger sensitivity in these patients with severe respiratory muscle weakness unless, as demonstrated by Parthasarathy and coworkers (32), the recruitment of the expiratory muscles interferes with the ability of the next inspiratory effort to trigger the ventilator. Other factors, such as a high level of PEEPe or over-assistance with a higher tidal volume leading to dynamic hyperinflation, may also be implicated in the genesis of ineffective inspiratory efforts (33eC36).
The main clinical goal for long-term NIMV is to reduce PaCO2, and this is usually achieved with "large" tidal volumes, which may result in "over-assistance" in some patients. This leads to the large amount of ineffective efforts and central apneas during sleep, producing sleep disruption, as demonstrated in our study (37, 38). In our study, central apneas occurred in those patients with higher mechanical inspiratory support during US ventilation and were dramatically reduced after the adjustment of the inspiratory support made during the PHYS ventilation. Over-assistance is not easily appreciated from simple clinical observation, sometimes only being apparent from direct observation of the Pdi signal, and it is not necessarily associated with daytime asynchrony (indeed, only three of our patients showed this phenomenon while awake).
Our study shows that the "wrong" settings of home ventilation can be more easily picked up from careful reading of sleep studies.
Thus, although analysis of respiratory mechanics is limited to a few specialized centers, sleep studies are commonly performed in a typical respiratory unit, so that in clinical practice it may be feasible useful to validate the US settings by performing a sleep study, reserving recordings of respiratory mechanics for very selected patients (e.g., the patient whose data are shown in Figure 2).
Limitations of the Study
Potential criticisms of the study are the small number of patients and the lack of long-term clinical assessment of the two different settings. Given the invasive nature of the procedures involved (i.e., recording respiratory mechanics), we limited the number of participants in this physiologic study, performed to gain basic information about a suitable protocol to be used in a subsequent clinical study. Last, despite the fact that the nine patients had different neuromuscular disorders, we have chosen a priori only certain kinds of pathologies that have been shown to impair specifically the respiratory muscles (38).
Conclusions
Our study clearly demonstrates that the empirical setting of ventilator during wakefulness is effective in improving gas exchange, but that it may cause patienteCventilator asynchrony during sleep, and this is associated with sleep disruption. These abnormalities are minimized when a physiologic setting, based on recordings of inspiratory muscle efforts, is applied. We conclude that a sleep study should be used to test the validity of the ventilator setting determined during wakefulness in patients with neuromuscular disorders embarking on a home nocturnal NIMV program.
This study was supported by a grant from Telethon Italy # 1125 C.
This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org
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Department of Clinical Neurology and Child Psychiatry, IRCCS C. Mondino, Pavia, Italy
ABSTRACT
Patients with neuromuscular disease (NMD) who require long-term ventilation normally have the ventilation set using empirical daytime parameters. We evaluated arterial blood gases (ABG), breathing pattern, respiratory muscle function, and sleep architecture during ventilation with two noninvasive Pressure Support Ventilation (nPSV) settings in nine patients with NMD. The two settings were randomly applied: the usual (US), with the nPSV setting titrated on simple clinical parameters, and the physiological (PHYS), tailored to the patient's respiratory effort. During wakefulness, nPSV significantly improved ABG and minute ventilation and reduced the diaphragmatic pressure-time product (PTPdi/breath), independently of the type of setting (PTPdi/breath spontaneous breathing 5.7 ± 2.4, US 3.2 ± 2, PHYS 3.6 ± 1.6 cm H2O · seconds-1, p < 0.001). However, during sleep, PHY nPSV resulted in a significant improvement of gas exchange, sleep efficiency (71.7% ± 14 US vs. 80.6% ± 8.3 PHYS, p < 0.01) and % of REM sleep (9.1% ± 7 US vs. 17.3% ± 5.4 PHYS, p < 0.01). This improvement was significantly correlated with the reduction in ineffective efforts. In NMD, nPSV is effective in improving daytime ABG and in unloading inspiratory muscles independently of whether it is set on the basis of the patient's comfort or the patient's respiratory mechanics. However, PHYS was associated with better sleep architecture and nighttime gas exchange.
Key Words: noninvasive mechanical ventilation; sleep; polysomnography; respiratory failure; home care
Noninvasive mechanical ventilation (NIMV) is being increasingly used as a treatment for chronic hypercapnic respiratory failure. Its use in patients affected by restrictive thoracic disorders, and in particular in patients with neuromuscular disease, suggested that it alleviates symptoms of chronic hypoventilation in the short term and, according to two small studies, may prolong survival (1eC5). Indeed, a recent Cochrane review stated that "long-term mechanical ventilation should be offered as a therapeutic option to patients with chronic hypercapnic respiratory failure due to neuromuscular diseases" (6). Daytime hypercapnia worsens during sleep, so that the major goal to achieve with the ventilatory treatment, in patients with neuromuscular disease, is the correction of nocturnal hypoventilation (6eC9). When the decision to initiate long-term NIMV is made, the ventilatory parameters to use during the nighttime are mainly determined empirically, based on patient's tolerance when awake and diurnal arterial blood gas variations. No study has so far investigated the possible influence of different ventilator settings, decided a priori according to daytime parameters, on sleep architecture and gas exchange. Indeed, in awake patients with COPD, the empirical setting was shown to parallel, at least to a certain extent, the respiratory muscle unloading and gas exchange achieved when the ventilator was physiologically titrated (10), but was also associated with a significantly higher prevalence of ineffective efforts (i.e., patients' inspiratory efforts unable to trigger the ventilator). In patients with severe respiratory muscle weakness, patienteCventilator dyssynchrony may be a cause of suboptimal ventilation, especially during the nighttime, when profound modifications in the recruitment of the respiratory muscle may occur during the various stages of sleep. The aim of this study was to compare the effects of two ventilation settings on sleep architecture and patienteCventilator interaction in patients already established on long-term mechanical ventilation for neuromuscular disorders. The ventilation settings were the "usual" (US) clinically determined setting and a "physiological" (PHYS) setting based on the recordings of inspiratory muscle effort. Some of the results of this study have been previously reported in the form of an abstract (11).
METHODS
Patients
We studied nine inpatients affected by chronic respiratory failure or nocturnal hypoventilation due to miscellaneous neuromuscular disorders who were admitted during a period of clinical stability for a follow-up control. All of the patients were already established on long-term NIMV. The local Ethics Committee approved the study and the patients gave written formal consent.
Home Mechanical Ventilation
Home noninvasive pressure support ventilation (nPSV) was provided by a portable ventilator and delivered through a nasal mask, except in one patient in whom a full-face mask was alternated with nasal pillows (see online supplement for details). The nPSV had been set at the maximal tolerated inspiratory pressure support able to reduce the awake PaCO2 by more than 5% of that recorded during spontaneous breathing (SB). A preset level of external positive end-expiratory airway pressure (PEEPe) was added. After setting the inspiratory pressure, the level of PEEPe was progressively increased in each patient, according to his or her tolerance.
Measurements
We measured static and dynamic lung volumes, arterial blood gases, and the respiratory pattern. Respiratory mechanics and the respiratory muscles function were assessed using standardized techniques described in detail in the online supplement (12eC15). Respiratory mechanics were assessed using Mead and Wittenberger's technique (12). Inspiratory pulmonary resistance (RL) and elastance (EL) were calculated by fitting the equation of motion of a single-compartment model using multilinear regression. Dynamic positive end-expiratory pressure (PEEPidyn) was obtained from the transdiaphragmatic pressure (Pdi) signal, as the value of Pdi at the moment of zero flow (13).
Daytime Measurements
In the morning of Day 1, patients were asked to breathe spontaneously through the pneumotachograph and were then randomized for 30 minutes of nPSV administered using the following two settings, already described in detail a previous study (10), separated by 20 minutes of unsupported breathing. This period was long enough to bring all the physiologic variables measured back to baseline values.
US. This is the setting described for home mechanical ventilation.
PHYS. This setting provides an inspiratory aid sufficient to reduce the Pdi tidal swing by more than 40% and less than 80% and/or to avoid any positive deflection in Pes during expiration. PEEPe was set at approximately 80% of the PEEPidyn recorded during spontaneous breathing.
All physiologic signals were recorded in the last 5 minutes of each unassisted or assisted breathing period.
This trial was performed using a home care ventilator that allowed us to set the PEEPe at zero (Helia; Saime, Savigny-le Temple, France). All signals were collected using a personal computer equipped with an A/D board, and stored at a sampling rate of 100 Hz.
Arterial blood was sampled from the radial artery at the end of the initial unassisted breathing period and at the end of each period of NIMV with the different settings.
Nighttime Measurements
On two consecutive nights after Day 1, each patient underwent, in random order, two different sleep studies during nPSV using US or PHYS settings.
Full standard night polysomnography (Sleep Lab 1000e; Jaeger, Hochberg, Germany) was performed using standard procedures and scored manually according to Rechtschaffen and Kales' criteria (16). Arousals were scored according to the criteria of the American Sleep Disorders Association (17). All the patients were acclimatized before to the sleep study setting, because they had performed a baseline sleep study before the enrollment in the home NIMV program.
Statistical Analysis
Results are presented as mean and SD. Variations in physiologic indices between spontaneous breathing, US, and PHYS were analyzed using MANOVA analysis; post hoc comparison was made to assess differences within treatments. A p value < 0.05 was chosen as the threshold of statistical significance for this test. The relationships between the variables were evaluated by Pearson's product-moment correlation coefficient. All the analyses were performed using the STATISTICA/W statistical package (Tulsa, OK), and a p value < 0.05 was considered statistically significant.
RESULTS
All the patients tolerated the procedure and completed the study. The patients' characteristics at the time of study, arterial blood gases at enrollment in the home mechanical ventilation program, and the total duration of the program are shown in Table 1.
Daytime Studies
Individual differences in inspiratory and expiratory pressures between US and PHYS are shown in Figures 1A and 1B, and in Table E1 in the online supplement. No significant difference was observed for the inspiratory pressure during US and PHYS. In contrast, a statistically significant difference was found between the mean PEEPe during US and PEEPe during PHYS (Table E1). In comparison with the US, the PHYS resulted in a higher inspiratory pressure in three patients (33.3%) and PEEPe was reduced in three patients.
Table 2 reports data on the respiratory pattern, arterial blood gas concentrations, and respiratory mechanics recorded during spontaneous breathing and during both US and PHYS mechanical ventilation. nPSV significantly improved minute ventilation by increasing tidal volume and reducing the respiratory rate, and likewise significantly improved both PaO2 and PaCO2, independently of the settings used. Finally, the two settings of ventilation considered did not produce statistically different daytime patterns of breathing, blood gases, or respiratory mechanics.
Table 2 also illustrates the mean values of diaphragm function and PEEPidyn recorded in the three experimental conditions. Compared with SB, both ventilator settings induced significant reductions in all the variables of diaphragm effort, as assessed by Pditidal, PTPdi/min, PTPdi/b, and PTPdi/VT.
During ventilation administered with the US, we observed variable degree of Pdi reduction, but one patient had a higher Pditidal during nPSV than during SB. Interestingly, this patient was ventilated with a PEEPe of 4 cm H2O, in the absence of any PEEPidyn during SB (Figure 2).
All patients but three were ventilated during US with a PEEPe higher than the PEEPidyn. The PHYS significantly reduced the amount of PEEPidyn.
While awake, two patients ventilated with the US and one with the PHYS showed ineffective efforts; this difference between treatments was not significant. The prevalence of these efforts in the total respiratory cycles was negligible with both ventilatory settings (8% and 11% with US and PHYS, respectively).
Nighttime Studies
Table 3 reports polysomnographic data obtained during US and PHYS nocturnal ventilation. The sleep study performed during US ventilation showed reduced sleep efficiency and percentage of REM sleep; furthermore, two patients did not have REM sleep. Nocturnal gas exchange was significantly impaired, as demonstrated by the sleep time spent with SaO2 less than 90% and the desaturation index. PHYS ventilation significantly improved sleep quality by increasing sleep efficiency and the amount of REM sleep, reducing the arousal index and improving gas exchange; furthermore, REM sleep was recorded in all patients.
During sleep with US ventilation, all but two patients showed ineffective efforts during non-REM (NREM) sleep (range 36eC240 events/hour). As shown in Table 3, during PHYS ventilation we observed a statistically significant lower number of ineffective efforts index during NREM sleep as compared with US ventilation; ineffective efforts were completely eliminated in three patients during PHYS ventilation. When we excluded these three patients from the analysis, the remaining six patients still had a statistically significant reduction of ineffective-effort index from 91.7 ± 98 to 31.7 ± 19.6 (p < 0.05). In all patients, the improvement of sleep quality, expressed by increased REM sleep (% of total sleep time), was strongly correlated to the reduction of ineffective efforts (r = eC0.82, p = 0.02; Figure 3).
During US ventilation, three patients had episodes of central apnea (central apnea index /> 5 events/hour; range, 5eC33 events/hour), associated with episode of oxygen desaturation, whereas during PHYS ventilation only one patient showed persistence of central apnea (6.3 events/hour). Both during US and PHYS ventilation a negative correlation was found between central apnea index and amount of REM sleep (expressed as % of total sleep time) (r = eC0.79, p < 0.05; r = eC0.83, p < 0.05, respectively). It is worth noting that the PHYS lowered the nPSV value in patients with central apneas: the difference in nPSV between patients ventilated with the PHYS and US, although not statistically significant, was eC2.25 ± 2.9 cm H2O in patients with central apneas and 0.5 ± 4 cm H2O in those without central apneas during US ventilation.
DISCUSSION
This study shows that, in stable patients with neuromuscular disorders, the settings of NIMV chosen on an empirical basis while the patient is awake do not predict ventilator synchrony while asleep, and that an incorrect titration of inspiratory support or PEEPe may impede the trigger of the mechanical breath. A physiological setting, based on recording the inspiratory efforts, may minimize the rate of ineffective efforts, resulting in improvement of sleep quality and gas exchange. During wakefulness, both settings are effective in improving arterial blood gases and in unloading inspiratory muscles.
Our results therefore suggest that when a patient with nocturnal hypoventilation enters a home ventilation program, the efficacy of the nPSV should be tested by polysomnography to verify the effect of the settings defined during daytime.
Daytime Studies
US settings of NIMV resulted in all but one patient (89%) having a level of inspiratory assistance sufficient to reduce the Pdi by more than 40% of that recorded during SB; this "success rate" is higher than that recorded in patients with COPD (65%) (10).
In patients with neuromuscular disorders, the titration of PEEPe seems to be more critical than that of the inspiratory pressure, because these patients may have either a negligible levels of PEEPidyn (< 1 cm H2O) or values higher than 2 cm H2O, which may be considered the limit for applying PEEPe in an attempt to minimize the inspiratory load due the presence of PEEPidyn (18). Considering the severe weakness of these patients' respiratory muscles, the lack of compensation of this resistive threshold may contribute to worsening the load/capacity balance per breath (i.e., the amount of Pdi generated per single breath, compared with the maximal Pdi) and, on the other hand, decrease the trigger sensitivity. In this respect, three of our patients had ineffective efforts while awake.
Conversely, the titration of PEEPe is also critical in patients not showing any PEEPidyn. Most of the so-called "bilevel" ventilators designed specifically for home NIMV are provided with a continuous air flow, so that a positive pressure of 2 cm H2O is delivered continuously, including during the expiratory phase. The application of this minimal PEEPe in the absence of dynamic hyperinflation may be followed by recruitment of the expiratory muscles (19), as illustrated for a representative patient in Figure 2.
Nighttime Studies
Sleep might worsen respiratory function in patients with chronic neuromuscular disorders. Sleep architecture may be altered with a high percentage of sleep in stage 1 and 2, a low percentage of slow wave sleep and/or REM sleep (20), and a high number of arousals related to oxygen desaturation episodes (21).
The effect of NIMV on sleep quality is varied because, although sleep appeared to be improved in different studies, it rarely became normal (4, 21eC26). The ventilator setting seems to be crucial to improve sleep quality and gas exchange. In fact, in this study we found that two different problems arose during nocturnal mechanical ventilation: a large number of ineffective breathing efforts in several patients and the occurrence of episodes of central apnea.
The improvement of sleep quality during PHYS setting was demonstrated by an increased amount of REM sleep and reduced number of arousals. The increasing percentage of REM sleep observed during PHYS ventilation was correlated with the reduction in ineffective efforts.
A phenomenon of missing or ineffective efforts (i.e., Pdi swings unable to trigger the ventilator) has been shown to occur quite often in ventilator-dependent patients with COPD (15). High resistance to airflow, PEEPidyn, low elastic recoil, high ventilatory demands, and short expiratory time on the ventilator has been advocated to explain this phenomenon in mechanically ventilated patients. We found that, when awake, patients with neuromuscular disease had a negligible amount of patienteCventilator mismatching, probably due to the different mechanical properties. However, this scenario changed considerably during sleep, when the prevalence of ineffective efforts became higher, particular when the patients were receiving ventilation set according to the usual clinical parameters. The PHYS settings resulted in a complete disappearance of the dyssinchrony in three patients and in a significant reduction in the remaining ones. This phenomenon has not been previously described, perhaps because of the different type of ventilation used in the past. The type of mechanical ventilation generally chosen in previous studies was the assist-control mode (22, 23, 27, 28) or a pressure control with a back-up respiratory rate so that the patients' respiratory rate during sleep was the same as the back-up rate of the ventilator (29). In our study, patients received bilevel ventilation in a spontaneous mode so that spontaneous respiratory activity was needed to maintain adequate minute ventilation. The potential benefit of timed versus spontaneous modes of ventilation have not been ever assessed in details, as stated by the Consensus Conference on Clinical Indications for Noninvasive Positive Pressure Ventilation in Chronic Respiratory Failure Due to Restrictive Lung Disease, COPD, and Nocturnal Hypoventilation (30).
Factors that could contribute to onset of ineffective efforts may differ from patient to patient: reduction in respiratory drive, reduction in respiratory muscle strength, increased inspiratory load due to augmented upper airway resistance, and mouth leaks may all contribute to the inability to trigger the ventilator adequately (7, 24, 31). In particular, the reduced amount of PEEPidyn with PHY settings may have contributed to improving the trigger sensitivity in these patients with severe respiratory muscle weakness unless, as demonstrated by Parthasarathy and coworkers (32), the recruitment of the expiratory muscles interferes with the ability of the next inspiratory effort to trigger the ventilator. Other factors, such as a high level of PEEPe or over-assistance with a higher tidal volume leading to dynamic hyperinflation, may also be implicated in the genesis of ineffective inspiratory efforts (33eC36).
The main clinical goal for long-term NIMV is to reduce PaCO2, and this is usually achieved with "large" tidal volumes, which may result in "over-assistance" in some patients. This leads to the large amount of ineffective efforts and central apneas during sleep, producing sleep disruption, as demonstrated in our study (37, 38). In our study, central apneas occurred in those patients with higher mechanical inspiratory support during US ventilation and were dramatically reduced after the adjustment of the inspiratory support made during the PHYS ventilation. Over-assistance is not easily appreciated from simple clinical observation, sometimes only being apparent from direct observation of the Pdi signal, and it is not necessarily associated with daytime asynchrony (indeed, only three of our patients showed this phenomenon while awake).
Our study shows that the "wrong" settings of home ventilation can be more easily picked up from careful reading of sleep studies.
Thus, although analysis of respiratory mechanics is limited to a few specialized centers, sleep studies are commonly performed in a typical respiratory unit, so that in clinical practice it may be feasible useful to validate the US settings by performing a sleep study, reserving recordings of respiratory mechanics for very selected patients (e.g., the patient whose data are shown in Figure 2).
Limitations of the Study
Potential criticisms of the study are the small number of patients and the lack of long-term clinical assessment of the two different settings. Given the invasive nature of the procedures involved (i.e., recording respiratory mechanics), we limited the number of participants in this physiologic study, performed to gain basic information about a suitable protocol to be used in a subsequent clinical study. Last, despite the fact that the nine patients had different neuromuscular disorders, we have chosen a priori only certain kinds of pathologies that have been shown to impair specifically the respiratory muscles (38).
Conclusions
Our study clearly demonstrates that the empirical setting of ventilator during wakefulness is effective in improving gas exchange, but that it may cause patienteCventilator asynchrony during sleep, and this is associated with sleep disruption. These abnormalities are minimized when a physiologic setting, based on recordings of inspiratory muscle efforts, is applied. We conclude that a sleep study should be used to test the validity of the ventilator setting determined during wakefulness in patients with neuromuscular disorders embarking on a home nocturnal NIMV program.
This study was supported by a grant from Telethon Italy # 1125 C.
This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org
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