Is Weaning Failure Caused by Low-Frequency Fatigue of the Diaphragm?
Division of Pulmonary and Critical Care Medicine, Edward Hines Jr. Veterans Administration Hospital, and Loyola University of Chicago Stritch School of Medicine, Hines, Illinois7wl, http://www.100md.com
ABSTRACT7wl, http://www.100md.com
TOP7wl, http://www.100md.com
ABSTRACT7wl, http://www.100md.com
INTRODUCTION7wl, http://www.100md.com
METHODS7wl, http://www.100md.com
RESULTS7wl, http://www.100md.com
DISCUSSION7wl, http://www.100md.com
REFERENCES7wl, http://www.100md.com
Because patients who fail a trial of weaning from mechanical ventilation experience a marked increase in respiratory load, we hypothesized that these patients develop diaphragmatic fatigue. Accordingly, we measured twitch transdiaphragmatic pressure using phrenic nerve stimulation in 11 weaning failure and 8 weaning success patients. Measurements were made before and 30 minutes after spontaneous breathing trials that lasted up to 60 minutes. Twitch transdiaphragmatic pressure was 8.9 ± 2.2 cm H2O before the trials and 9.4 ± 2.4 cm H2O after their completion in the weaning failure patients (p = 0.17); the corresponding values in the weaning success patients were 10.3 ± 1.5 and 11.2 ± 1.8 cm H2O (p = 0.18). Despite greater load (p = 0.04) and diaphragmatic effort (p = 0.01), the weaning failure patients did not develop low-frequency fatigue probably because of greater recruitment of rib cage and expiratory muscles (p = 0.004) and because clinical signs of distress mandating the reinstitution of mechanical ventilation arose before the development of fatigue. Twitch pressure revealed considerable diaphragmatic weakness in many weaning failure patients. In conclusion, in contrast to our hypothesis, weaning failure was not accompanied by low-frequency fatigue of the diaphragm, although many weaning failure patients displayed diaphragmatic weakness.
Key Words: ventilator weaning • respiratory muscles • muscle fatigue • phrenic nerve • respiratory insufficiencyii2+j, 百拇医药
INTRODUCTIONii2+j, 百拇医药
TOPii2+j, 百拇医药
ABSTRACTii2+j, 百拇医药
INTRODUCTIONii2+j, 百拇医药
METHODSii2+j, 百拇医药
RESULTSii2+j, 百拇医药
DISCUSSIONii2+j, 百拇医药
REFERENCESii2+j, 百拇医药
When a mechanical load on the respiratory system is too large or continues for too long of a time, the respiratory muscles can develop contractile fatigue (1). In the context of neurophysiology, fatigue represents a decrease in muscle force in response to a given neural stimulus. Contractile fatigue can be short or long lasting. Short-lasting fatigue, also known as high-frequency fatigue, results from accumulation of inorganic phosphate (2), failure of the membrane electrical potential to propagate beyond T tubes (3), and to a lesser extent intramuscular acidosis (4). Long-lasting fatigue (5), also known as low-frequency fatigue, is consistent with the development of and recovery from muscle injury (6, 7), and it can persist for days. Contractile fatigue can be induced in healthy subjects under constrained experimental conditions when subjects willingly continue to generate large subatmospheric swings in intrathoracic pressure irrespective of afferent signals from the respiratory muscles or elsewhere (5, 8, 9).
Patients who fail a trial of weaning from mechanical ventilation are at a considerable risk for developing respiratory muscle fatigue. Much circumstantial evidence suggests that these patients do develop contractile fatigue (10–15). For example, we found that 5 of 17 weaning failure patients experienced an imbalance between mechanical load and respiratory muscle capacity, expressed as a tension–time index (TTdi), which would be expected to induce contractile muscle fatigue (13). None of the experimental techniques used to date, however, provide direct evidence of contractile fatigue, and it is still unknown whether contractile fatigue occurs in patients..e, 百拇医药
The question of whether respiratory muscle fatigue occurs in weaning failure patients is of major clinical importance. Patients who fail a trial of weaning are at a disadvantage when compared with weaning success patients because they have greater abnormalities in lung mechanics (13–15). If these patients also develop contractile fatigue of their respiratory muscles during a failed weaning trial, the superimposed structural injury is likely to set them back in their clinical course. The new injury might even become the ultimate determinant of whether some patients are ever successfully weaned from the ventilator.
The most direct method for detecting fatigue in patients is to stimulate the phrenic nerves and measure the resulting change in transdiaphragmatic pressure. We used this approach to test the hypothesis that patients who fail a trial of weaning from the mechanical ventilation develop contractile fatigue of the diaphragm, whereas successfully weaned patients do not. Some the results of these studies have been previously reported in the form of abstracts (16, 17).jg8u, 百拇医药
METHODSjg8u, 百拇医药
TOPjg8u, 百拇医药
ABSTRACTjg8u, 百拇医药
INTRODUCTIONjg8u, 百拇医药
METHODSjg8u, 百拇医药
RESULTSjg8u, 百拇医药
DISCUSSIONjg8u, 百拇医药
REFERENCESjg8u, 百拇医药
Patientsjg8u, 百拇医药
Nineteen patients whose primary physician considered them ready for weaning were recruited (see online supplement). Appropriate institutional review boards approved the study, and written consents were obtained.
fig.ommitted-?|, http://www.100md.com
TABLE 1. Weaning success-?|, http://www.100md.com
Experimental Setup-?|, http://www.100md.com
Flow and pressure measurements.-?|, http://www.100md.com
Flow and airway, esophageal (Pes), gastric (Pga), and transdiaphragmatic (Pdi) pressures were measured (see online supplement for further details).-?|, http://www.100md.com
Compound diaphragmatic action potentials.-?|, http://www.100md.com
Compound diaphragmatic action potentials were recorded bilaterally using surface electrodes. Single bilateral phrenic nerve stimulation was performed using two magnetic stimulators with two sets of double 40-mm coils that generated a magnetic field of 3.2 Tesla at maximal output (see online supplement for further details).-?|, http://www.100md.com
Protocol-?|, http://www.100md.com
Twitch stimulation before the weaning trial.-?|, http://www.100md.com
To avoid twitch potentiation (5, 18), the patients received controlled ventilation for 20 minutes before delivering the first stimulation. Six to 15 stimulations were then delivered bilaterally at intervals of approximately 15 seconds at end exhalation while closing the inline valve. After the last stimulation, maximal voluntary inspiratory efforts were recorded during a 20-second occlusion of the airway (19) (see online supplement for details).
Trial of spontaneous breathing.+/0, http://www.100md.com
The weaning trial was conducted for up to 1 hour as tolerated. In eight weaning failure and four weaning success patients, arterial blood samples were obtained at 2 minutes and at the end of the trial. Patients who did not develop criteria of weaning failure (13, 20) (see online supplement for criteria) were extubated. Patients who sustained spontaneous breathing for more than 24 hours were deemed the weaning successes group (21). The remaining patients, the weaning failure group, required mechanical ventilation for 3 days to more than 57 days after the study.+/0, http://www.100md.com
Twitch stimulation after the trial.+/0, http://www.100md.com
After the weaning trial, all patients, irrespective of the weaning outcome, were returned to mechanical ventilation for 30 minutes. At the end of this period, twitch Pdi and maximal voluntary inspiratory efforts were measured. To determine whether maximal depolarization of the phrenic nerve was achieved, progressively increasing outputs from the stimulator were delivered in 12 patients (see online supplement for details). Thereafter, patients who had met the a priori criteria of weaning failure were maintained on mechanical ventilation, whereas the remaining patients were extubated.
Twitch interpolation.}j&4[, 百拇医药
Twitch interpolation measurements were performed in seven patients before and after the weaning trial (22) (see online supplement for details).}j&4[, 百拇医药
Physiologic Measurements}j&4[, 百拇医药
Transdiaphragmatic twitch pressure.}j&4[, 百拇医药
Twitch Pdi was measured as the difference between the maximum Pdi displacement secondary to phrenic nerve stimulation and the value immediately before stimulation (18, 23). Criteria for acceptable twitch responses are listed in the online supplement. The within-occasion coefficient of variation of twitch Pdi before and after weaning was 10% or less in 17 patients, and it was within 12 and 14% in the remaining 2 patients. Data collected after the weaning trial did not satisfy the a priori criteria for acceptable twitch responses in 3 of the 19 patients, and they were excluded from data analysis.}j&4[, 百拇医药
Maximum voluntary inspiratory pressure.
The pressure developed by the diaphragm was computed as the maximal excursion in Pdi (Pdimax) during the 20-second occlusions (19).xv@k, http://www.100md.com
Respiratory mechanics and effort indices.xv@k, http://www.100md.com
Inspiratory resistance of the lung, dynamic compliance of the lung, and intrinsic positive end-expiratory pressure (PEEPi) were computed according to standard formulae (24–27). Pressure-time product (PTPdi) and TTdi of the diaphragm were quantified using standard formulae (1, 26–28). The relative contribution of the different respiratory muscles to tidal breathing was assessed as the ratio of swings in Pga to swings in Pes (Pga/Pes) (see online supplement for calculation of these variables).xv@k, http://www.100md.com
Data Analysisxv@k, http://www.100md.com
Analysis of variance and t tests were used as needed (see online supplement). Some measurements are included in another manuscript (29).xv@k, http://www.100md.com
RESULTSxv@k, http://www.100md.com
TOP
ABSTRACTa9swzq., http://www.100md.com
INTRODUCTIONa9swzq., http://www.100md.com
METHODSa9swzq., http://www.100md.com
RESULTSa9swzq., http://www.100md.com
DISCUSSIONa9swzq., http://www.100md.com
REFERENCESa9swzq., http://www.100md.com
Nine patients met the a priori criteria for weaning failure after 44 ± 7 minutes of spontaneous breathing, and mechanical ventilation was reinstituted. Seven patients tolerated a trial of 60 minutes without distress and were extubated.a9swzq., http://www.100md.com
At the beginning of the weaning trial, PaO2, PaCO2, and pH were not different between the groups . By the end of the trial, a small decrease in pH (p = 0.025) occurred in the failure group, and no significant change occurred in the success group.a9swzq., http://www.100md.com
fig.ommitteda9swzq., http://www.100md.com
TABLE 2. Alterations in arterial blood gas measurementsa9swzq., http://www.100md.com
Twitch and Maximal Inspiratory Pressuresa9swzq., http://www.100md.com
Magnetic stimulation elicited twitch pressures in all patients . Before the weaning trial, twitch Pdi was 8.9 ± 2.2 cm H2O in the failure group and 10.3 ± 1.5 cm H2O in the success group (p = 0.63) . After the trial, twitch Pdi was 9.4 ± 2.4 in the failure group and 11.2 ± 1.8 cm H2O in the success group (p = 0.58); these values were not different from the values for each group before the trial. (In the failure patient who had a malfunctioning gastric balloon, twitch Pes was -20.6 ± 0.6 cm H2O before and -18.2 ± 0.6 cm H2O after the trial.) Before the trial, Pdimax was 39.4 ± 6.6 cm H2O in the failure group and 55.2 ± 8.2 cm H2O in the success group (p = 0.36) . The values of Pdimax at 30 minutes after the trial were 41.0 ± 6.8 cm H2O in the failure group and 53.5 ± 8.3 cm H2O in the success group (p = 0.26); these values were not different from the values for each group before the trial.
fig.ommittedor\ot), 百拇医药
Figure 1. Pes, Pga, Pdi, and compound motor action potentials (CAMP) of the right and left hemidiaphragms after phrenic nerve stimulation before (left) and after (right) a failed trial of weaning. The end-expiratory value of Pes and the amplitude of the right and left CAMPs were the same before and after the trial, indicating that the stimulations were delivered at the same lung volume and that the stimulations achieved the same extent of diaphragmatic recruitment. The amplitude of twitch Pdi elicited by phrenic nerve stimulation was the same before and after weaning.or\ot), 百拇医药
fig.ommittedor\ot), 百拇医药
Figure 2. Transdiaphragmatic twitch pressure (twitch Pdi), recorded before and 30 minutes after a weaning trial in nine weaning failure patients (closed symbols, left panel) and seven weaning success patients (open symbols, right panel). Twitch Pdi did not differ between the groups before the trial, and it did not decrease after the trial in either group. Bars represent group mean ± SE.or\ot), 百拇医药
fig.ommittedor\ot), 百拇医药
Figure 3. Pdimax, recorded before and 30 minutes after a weaning trial, in nine weaning failure patients (closed symbols, left) and seven weaning success patients (open symbols, right). Pdimax did not differ between the groups before the trial, and it did not decrease after the trial in either group. Bars represent group mean ± SE.
Among the seven patients in whom twitch interpolation was performed, the amplitude of the compound diaphragmatic action potential during interpolation was less than that during passive conditions. A detectable superimposed twitch, however, was always present—even in those four patients in whom it was possible to time the superimposed stimulus at, or near to, Pdimax . This observation suggests that the phrenic nerve was not maximally stimulated by a "maximal" voluntary maneuver.m6@31, 百拇医药
fig.ommittedm6@31, 百拇医药
Figure 4. Continuous recordings of Pes, Pga, and Pdi during airway occlusion in a patient after a failed trial of weaning. Phrenic nerve stimulation (arrow) during the maximal inspiratory effort resulted in a detectable superimposed twitch. The presence of a superimposed twitch during a maximal effort indicates that voluntary activation of the diaphragm was incomplete.m6@31, 百拇医药
Diaphragmatic Pressure Output (PTPdi) and TTdim6@31, 百拇医药
At trial onset, PTPdi/min was 337 ± 51 cm H2O x seconds/minute in the failure group and 205 ± 27 cm H2O x seconds/minute in the success group . At the end of the trial, PTPdi/min increased to 523 ± 130 cm H2O x seconds/minute in the failure group (p < 0.05) and to 367 ± 64 cm H2O x seconds/minute in the success group (p < 0.01). Over the course of the trial, PTPdi/min did not differ between the two groups (p = 0.18).
fig.ommittedhm:m, 百拇医药
Figure 5. PTPdi (left panel) and TTdi of the diaphragm (right panel) during a weaning trial in the failure (closed symbols) and success (open symbols) groups. Between the onset and the end of the trial, increases in PTPdi (p < 0.005) and TTdi (p < 0.005) occurred in both groups. Over the course of the trial, the failure group had higher values of TTdi (p = 0.01) but not of PTPdi (p = 0.18) than did the success group. Bars represent SE.hm:m, 百拇医药
Over the course of the trial, TTdi was higher in the failure group than in the success group (p = 0.01) . Of the nine failure patients, seven had a TTdi at or above 0.15 (the putative threshold for task failure and fatigue) during two or more isotimes. Of the seven success patients, only one had a TTdi at or above 0.15 during two isotimes.hm:m, 百拇医药
Ribcage and Expiratory Muscle Recruitmenthm:m, 百拇医药
At trial onset, the Pga/Pes ratio was greater in the failure group than in the success group: -0.03 ± 0.04 versus -0.19 ± 0.05 (p = 0.002)
. Over the course of the trial, Pga/Pes remained greater in weaning failure patients (p = 0.004). At the end of the trial, the ratio had increased to 0.12 ± 0.07 in the failure group (p = 0.05). At the end of the trial, the ratio in the success group was -0.10 ± 0.02. Because patients with diaphragmatic paralysis can have enhanced rib cage muscle recruitment even in the absence of respiratory distress (30), Pga/Pes ratio of the failure patients was compared with that of the success patients after excluding the two patients (both weaning failure patients) with hemidiaphragmatic paralysis. The Pga/Pes was still greater in the weaning failure patients (p = 0.01)—a finding similar to the overall group.)c@5{:, http://www.100md.com
fig.ommitted)c@5{:, http://www.100md.com
Figure 6. Pga/Pes—an index of rib cage and expiratory muscle contribution to respiratory effort—during a weaning trial in the failure (closed symbol) and success (open symbol) groups. Between the onset and the end of the trial, Pga/Pes increased in the failure (p = 0.04) and success groups (p = 0.05), and the ratio was higher in the failure group than in the success group over the course of the trial (p = 0.004). Bars represent SE.
Respiratory Mechanics6;3up, 百拇医药
At onset of the trial, inspiratory resistance of the lung was not different between the failure and success groups: 12.8 ± 1.8 versus 10.4 ± 0.6 cm H2O/L/second (p = 0.44). During the course of the trial, inspiratory resistance of the lung in the failure group became greater than in the success group (p = 0.05) (data not shown). At trial onset, dynamic compliance of the lung was 55 ± 11 ml/cm H2O in the failure group and 184 ± 81 ml/cm H2O in the success group. During the course of the trial, dynamic lung compliance was lower in the failure group than that in the success group (p = 0.042) (data not shown).6;3up, 百拇医药
At onset of the trial, total PEEPi (not corrected for expiratory rise in Pga) was not different between the failure and success groups: 4.6 ± 1.3 versus 2.1 ± 0.4 cm H2O (p = 0.13). Likewise, corrected PEEPi (corrected for expiratory rise in Pga) was not different between the failure and success groups: 3.8 ± 1.2 versus 2.1 ± 0.4 cm H2O (p = 0.59). At the end of the trial, total PEEPi had increased to 11.6 ± 4.4 cm H2O (p = 0.03) in the failure group and to 4.4 ± 1.0 cm H2O (p = 0.001) in the success group. At the end of the trial, corrected PEEPi was 6.2 ± 3.6 cm H2O in the failure group. The values of total and corrected PEEPi in the success patients were nearly identical.
DISCUSSION17h4^, 百拇医药
TOP17h4^, 百拇医药
ABSTRACT17h4^, 百拇医药
INTRODUCTION17h4^, 百拇医药
METHODS17h4^, 百拇医药
RESULTS17h4^, 百拇医药
DISCUSSION17h4^, 百拇医药
REFERENCES17h4^, 百拇医药
This is the first report of systematic measurements of the contractile response of the diaphragm to phrenic nerve stimulation in patients being weaned from mechanical ventilation. We found that patients failing a weaning trial did not develop low-frequency fatigue.17h4^, 百拇医药
Researchers have long thought that some, if not most, patients who fail a weaning trial develop respiratory muscle fatigue (10, 12–15). The techniques used in previous studies were indirect (10–14), raising doubt as to whether fatigue truly occurred (31). We used a direct test of muscle fatigability, namely stimulation of the phrenic nerve and measurement of the resulting Pdi (32, 33). Even with this technique, data can be inaccurate because of several confounding variables: changes in lung volume, variation in the degree of neural depolarization achieved by the stimulator, and the contraction history of the muscle (i.e., twitch potentiation). We took particular care to avoid these confounding factors and excluded data that did not satisfy our a priori inclusion criteria. As such, we view the absence of a fall in twitch Pdi as evidence that low-frequency fatigue is not a mechanism of weaning failure.
Factors That Can Contribute to Fatigue{nv$et, 百拇医药
Diaphragmatic fatigue occurs only when there is a critical stress on the muscle. A critical stress can result from an increase in mechanical load, which leads to an increase in respiratory center output and thus increase in respiratory muscle pressure (PTPdi). When a patient's muscle strength is small, an increase in PTPdi is more likely to exceed the diaphragmatic threshold (TTdi) for fatigue (1).{nv$et, 百拇医药
At onset of the weaning trial, the weaning failure patients had abnormalities in lung mechanics comparable to those reported in previous studies: inspiratory resistance of the lung was 13 cm H2O/L/second versus 9 (13) and 22 cm H2O/L/second (14); dynamic lung compliance was 55 ml/cm H2O versus 48 (13) and 70 ml/cm H2O (14), and total PEEPi was 4.6 cm H2O versus 2.0 (13) and 5.9 cm H2O (14). By the end of the trial, inspiratory resistance of the lung (17 cm H2O/L/second) and total PEEPi (12 cm H2O) increased to or exceeded previously reported values (16 cm H2O/L/second and 4 cm H2O, respectively [13]). Dynamic lung compliance at the end of a failed trial was within the range of previously reported values: 48 ml/cm H2O versus 29 (13) and approximately 70 ml/cm H2O (14). Accordingly, our weaning failure patients displayed abnormalities in pulmonary mechanics equivalent to patients in previous studies. Our weaning failure patients displayed greater resistive and elastic loads than did our weaning success patients—a finding similar to our previous report (13).
The increase in PTPdi over the course of the weaning trial indicates that the respiratory centers attempted to defend alveolar ventilation in the face of deteriorating lung mechanics. This finding is consistent with our previous report of an increase in overall respiratory muscle pressure (esophageal pressure-time product [PTPe]) (13). In that previous study (13), the increase in PTPes was not sufficient to prevent hypercapnia in 13 of the 17 weaning failure patients. Hypercapnia was less common in this study: PaCO2 increased by 5 to 16 percent in three of eight weaning failure patients in whom arterial blood samples where obtained. Three factors may account for the difference in the two studies: baseline arterial samples were collected at approximately 2 minutes after the start of spontaneous breathing in this study, whereas they were collected during controlled mechanical ventilation in the previous study; only four weaning failure patients in this study had COPD as compared with all patients in the previous study, and respiratory muscle effort, as reflected by PTPes, was somewhat greater in this study than in the previous study (538 and 388 cm H2O x seconds/minute, respectively).
TTdi combines three key determinants of diaphragmatic fatigue: pressure generated by the diaphragm (PTPdi), muscle strength (Pdimax), and respiratory duty cycle (inspiratory time/total respiratory cycle time). In healthy subjects, a sustained increase in TTdi above 0.15 leads to diaphragmatic fatigue (1). The threshold of 0.15 was exceeded by 77% of our weaning failure patients and by 15% of our weaning success patients. However, no patient showed evidence of low-frequency fatigue. Three factors could explain why a high TTdi was not accompanied by fatigue: the heightened muscle effort was not sustained for a sufficient time; endurance of the diaphragm was greater in weaning failure patients than in healthy subjects; and the recorded value of TTdi was an overestimate.&|, http://www.100md.com
Bellemare and Grassino (1) reported that the relationship between TTdi and time to task failure in healthy subjects follows an inverse power function: time to task failure = 0.1 (TTdi)-3.6. The average duration of weaning trials in our failure patients was 44 minutes. The average values of TTdi for the first, second, third, and fourth quintiles of the trial durations were 0.17, 0.17, 0.22, and 0.22, respectively. Based on the formula of Bellemare and Grassino (1), the expected times to task failure for the respective quintiles would be 59, 59, 28, and 28 minutes. The average value of TTdi during the last minute of the trial was 0.26, and the weaning failure patients would be predicted to sustain this effort for another 13 minutes before developing task failure. These calculations suggest that weaning failure patients did not sustain the increase in load for a duration sufficient to cause low-frequency fatigue; that is, the trial was stopped because patients developed a priori–defined clinical manifestations of respiratory distress before they developed fatigue.
Fatigue is not an all-or-none phenomenon (34). Measuring twitch pressures after forceful voluntary contractions, so-called potentiated twitches, has been suggested as a means for detecting an early decrease in muscle contractility (34, 35). In eight patients (four weaning failure and four weaning success patients), we were able to record the potentiated twitches both before and after weaning by stimulating the phrenic nerves immediately after the patients performed maximal voluntary inspiratory efforts. Potentiated twitch Pdi was 8.6 ± 3.1 cm H2O before the trial and 8.7 ± 2.9 cm H2O after the trial in the four weaning failure patients; the corresponding values for nonpotentiated twitches were 6.9 ± 2.6 and 6.8 ± 2.4 cm H2O, respectively. Potentiated twitch Pdi was 10.5 ± 1.5 cm H2O before the trial and 10.6 ± 1.1 cm H2O after the trial in the four weaning success patients; the corresponding values for nonpotentiated twitches were 8.3 ± 1.5 and 8.7 ± 1.4 cm H2O, respectively. The failure of potentiated twitch Pdi to decrease after a failed weaning trial further supports our reasoning that the inspiratory load, even if it was in the fatiguing range, was not sustained for a sufficient length of time to cause fatigue.
If endurance of the respiratory muscles is supranormal in critically ill patients, fatigue would not develop at a TTdi of 0.15. Direct measurements of diaphragmatic endurance have not been obtained in critically ill patients, but circumstantial evidence suggests that it is not supranormal. Indeed, endurance of the diaphragm is decreased in stable patients with spinal cord injury (36), probably because fatigue-sensitive, type II myosin heavy chains are increased in the diaphragm (37).0s/, http://www.100md.com
Reliable calculation of TTdi is critically dependent on an accurate measurement of diaphragmatic strength. Our data show that even carefully made measurements of Pdimax commonly underestimate maximum strength. The pressure tracings in all of our patients during the Pdimax measurements had the characteristics of a Mueller maneuver: large negative excursions in Paw and Pes with slightly positive (or, in one patient, negative) deflections in Pga . In healthy subjects, the combination of a Mueller maneuver with an expulsive maneuver results in higher values of Pdimax (38), but critically ill patients have great difficulty in performing the combined maneuver. Moreover, the finding of twitch interpolation (that is, a measurable twitch Pdi when the phrenic nerves were stimulated during maximum voluntary effort) indicates that patients were not able to activate completely the diaphragm during a "maximum" maneuver (22) . The underestimation of Pdimax will necessarily produce an overestimate of TTdi, which further explains why patients did not develop low-frequency fatigue despite recorded values of TTdi above 0.15.
Defense Mechanisms against Low-Frequency Fatigue', http://www.100md.com
All of the weaning failure patients experienced severe respiratory distress, but none developed low-frequency fatigue. Three strategies may have protected the diaphragm against fatigue: increased rib cage and expiratory muscle recruitment, the early reinstitution of mechanical ventilation, and respiratory center downregulation.', http://www.100md.com
Immediately after the start of the weaning trial, the weaning failure patients displayed greater recruitment of rib cage and expiratory muscles during tidal breathing than did the weaning success patients (greater Pga/Pes) (Figure 6). (Excluding the two patients with hemidiaphragmatic paralysis does not affect this finding.) The same alteration in respiratory muscle recruitment has also been reported in patients (39–42) and volunteers (34, 43) when diaphragmatic effort is increased during tidal breathing. Recruitment of the rib cage and expiratory muscles appears to contribute to the development of dyspnea (41, 44). Clinicians also take increased activity of the rib cage and abdominal muscles into account in deciding whether to continue or interrupt a weaning trial.
The increase in PTPdi during the weaning trial signifies a progressive increase in respiratory motor output, as has been previously reported (14, 45, 46). Some patients, however, developed hypercapnia, suggesting that respiratory motor output may have been downregulated. Studies in animals show that a decrease in respiratory motor output occurs as a preterminal event (47) and a decrease in drive can be accompanied by the development of diaphragmatic fatigue at the time of apnea (48). Afferent signals originating in fatiguing muscles may activate neural pathways responsible for downregulation of respiratory motor output (49–52). Downregulation of respiratory drive will decrease metabolic demands and the likelihood of contractile fatigue (53). During the usual protocol for inducing respiratory muscle fatigue in healthy volunteers (achieving a target inspiratory pressure while breathing through a resistor [1, 5, 9]), the exhortation of the investigators and the volition of the subjects may override the afferent signals that downregulate respiratory drive (9). The artificial and constrained nature of this laboratory protocol is very different from the natural evolution of respiratory distress in weaning failure patients.
Other Causes of Weaning Failure9ikv};q, 百拇医药
Although low-frequency fatigue does not appear to be responsible for weaning failure, other abnormalities of the respiratory muscles may be causative. Possible mechanisms include diaphragmatic weakness, atrophy, high-frequency fatigue, and hyperinflation.9ikv};q, 百拇医药
In our laboratory, the mean amplitude of nonpotentiated twitch Pdi ranges from 35.4 to 38.9 cm H2O in healthy subjects (5, 23, 34) and from 17.2 to 20.1 cm H2O in stable patients with COPD (54, 41). Most of our weaning failure and weaning success patients had twitch Pdi values lower than the values recorded in ambulatory patients. Six weaning failure patients had twitch Pdi values of less than 10 cm H2O. These results suggest that many mechanically ventilated patients have diaphragmatic weakness and that some weaning failure patients have severe weakness.9ikv};q, 百拇医药
Eight weaning failure patients and six weaning success patients had infections (pneumonia or sepsis) while receiving ventilator support. Sepsis is known to cause diaphragmatic injury and weakness (55, 56). All of our patients had been ventilated with patient-triggered modes, and the involved muscle contractions may aggravate the diaphragmatic injury caused by sepsis (57). Several studies in experimental animals (58) demonstrate that mechanical ventilation can induce respiratory muscle atrophy, although it is not known whether this occurs in patients. Many ventilator-supported patients are malnourished (59), and this will further contribute to atrophy (60–62).
Our study does not directly address whether the patients developed high-frequency fatigue, as has been suggested (11). The lack of change in twitch Pdi and Pdimax does not exclude the possibility. High-frequency fatigue can resolve within 10 to 15 minutes (4, 53), and it could have disappeared by the time of testing (30 minutes after the end of the weaning trial).z(, 百拇医药
Weakness of the inspiratory muscles arises when patients develop progressive hyperinflation. An increase in end-expiratory volume causes shortening of inspiratory muscles and a decrease in force generation. Total PEEPi increased over the course of the trial in the weaning failure patients, but an indirect measurement of end-expiratory volume—PEEPi corrected for expiratory muscle recruitment (26)—revealed no change. Corrected PEEPi was also not different between weaning success and weaning failure patients, suggesting that hyperinflation did not increase during the trials.z(, 百拇医药
Clinical Implications
Respiratory muscle fatigue has been thought to be a common cause of weaning failure, and accordingly, clinical management has been directed toward improving the capacity of the respiratory muscles to generate (strength) and to sustain (endurance) force (63). Does the lack of low-frequency fatigue in our weaning failure patients mean that these strategies are misdirected? No. Many weaning failure patients have severe diaphragmatic weakness (66% had twitch Pdi values below 10 cm H2O), and weakness probably sets in motion the complex processes described in this study, which ultimately lead to the early reinstitution of mechanical ventilation.3, http://www.100md.com
Investigators have shown that respiratory muscle training can increase respiratory muscle strength and endurance in ambulatory patients, but the improvement has not been shown to achieve better clinical well-being or outcome (64, 65). The lack of benefit is not surprising because baseline maximum inspiratory pressure was not reduced to a level that hinders spontaneous breathing (66). In weaning failure patients, however, a small improvement in respiratory muscle strength and endurance could have a profound effect on clinical outcome. Based on the results of this study, it could prove useful to develop a training regimen that can achieve an improvement in twitch pressure (the noninvasive measurement of twitch airway pressure may satisfactorily substitute for twitch Pdi [29]). Such a training regimen could have a major benefit in the difficult-to-wean patients (63), although proof of this possibility requires a randomized control trial. Although the challenge of designing and undertaking such a trial will be considerable, the scientific motivation for such a study is stronger than before.
In summary, patients who fail a weaning trial displayed greater mechanical load than did weaning success patients. The increase in load caused TTdi to increase above the threshold associated with fatigue, yet twitch Pdi and Pdimax did not decrease in these patients. Factors that may have protected the diaphragm against fatigue include greater rib cage and expiratory muscle recruitment, downregulation of respiratory motor output, and early reinstitution of mechanical ventilation. In conclusion, in contrast to our hypothesis, weaning failure was not accompanied by low-frequency fatigue of the diaphragm, although many weaning failure patients displayed severe diaphragmatic weakness.[6q{'f, http://www.100md.com
REFERENCES[6q{'f, http://www.100md.com
TOP[6q{'f, http://www.100md.com
ABSTRACT[6q{'f, http://www.100md.com
INTRODUCTION[6q{'f, http://www.100md.com
METHODS[6q{'f, http://www.100md.com
RESULTS[6q{'f, http://www.100md.com
DISCUSSION[6q{'f, http://www.100md.com
REFERENCES[6q{'f, http://www.100md.com
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Laghi F, Jubran A, Parthasarathy S, Choe W, Segal JM, Tobin MJ. Can patients who fail a trial of weaning develop diaphragmatic fatigue [abstract]? Am J Respir Crit Care Med 2000;161:A790.oy|l*k+, http://www.100md.com
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Laghi F, Harrison MJ, Tobin MJ. Comparison of magnetic and electrical phrenic nerve stimulation in assessment of diaphragmatic contractility. J Appl Physiol 1996;80:1731–1742.5, 百拇医药
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Cattapan SE, Laghi F, Astor TL, Tobin MJ. Can diaphragmatic contractility be assessed by airway twitch pressure in mechanically ventilated patients [abstract]? Am J Respir Crit Care Med 2001;163:A754.&n, 百拇医药
Hart N, Nickol AH, Cramer D, Ward SP, Lofaso F, Pride NB, Moxham J, Polkey MI. Effect of severe isolated unilateral and bilateral diaphragm weakness on exercise performance. Am J Respir Crit Care Med 2002;165:1265–1270.&n, 百拇医药
Tobin MJ, Laghi F. Monitoring respiratory muscle function. In: Tobin MJ, editor. Principles and practice of intensive care monitoring. New York: McGraw-Hill; 1998. p. 497–544.&n, 百拇医药
Aubier M, Murciano D, Lecocguic Y, Viires N, Pariente R. Bilateral phrenic stimulation: a simple technique to assess diaphragmatic fatigue in humans. J Appl Physiol 1985;58:58–64.
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Laghi F, Topeli A, Tobin MJ. Does resistive loading decrease diaphragmatic contractility before task failure? J Appl Physiol 1998;85:1103–1112.:ad@$, 百拇医药
Mador MJ, Kufel TJ, Pineda LA, Steinwald A, Aggarwal A, Upadhyay AM, Khan MA. Effect of pulmonary rehabilitation on quadriceps fatigability during exercise. Am J Respir Crit Care Med 2001;163:930–935.:ad@$, 百拇医药
Nava S, Rubini F, Zanotti E, Caldiroli D. The tension-time index of the diaphragm revisited in quadriplegic patients with diaphragm pacing. Am J Respir Crit Care Med 1996;153:1322–1327.:ad@$, 百拇医药
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Gandevia SC, Gorman RB, McKenzie DK, Southon FC. Dynamic changes in human diaphragm length: maximal inspiratory and expulsive efforts studied with sequential radiography. J Physiol 1992;457:167–176.
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Ninane V, Yernault JC, De Troyer A. Intrinsic PEEP in patients with chronic obstructive pulmonary disease: role of expiratory muscles. Am Rev Respir Dis 1993;148:1037–1042.t+pw.3:, 百拇医药
Laghi F, Jubran A, Topeli A, Fahey PJ, Garrity ER Jr, Arcidi JM, de Pinto DJ, Edwards LC, Tobin MJ. Effect of lung volume reduction surgery on neuromechanical coupling of the diaphragm. Am J Respir Crit Care Med 1998;157:475–483.t+pw.3:, 百拇医药
Estenne M, Derom E, De Troyer A. Neck and abdominal muscle activity in patients with severe thoracic scoliosis. Am J Respir Crit Care Med 1998;158:452–457.t+pw.3:, 百拇医药
Yan S, Sliwinski P, Gauthier AP, Lichros I, Zakynthinos S, Macklem PT. Effect of global inspiratory muscle fatigue on ventilatory and respiratory muscle responses to CO2. J Appl Physiol 1993;75:1371–1377.t+pw.3:, 百拇医药
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Sassoon CS, Mahutte CK. Airway occlusion pressure and breathing pattern as predictors of weaning outcome. Am Rev Respir Dis 1993;148:860–866.lr9, http://www.100md.com
Ferguson GT. Effects of oxygenation and hypercapnia on diaphragmatic function and central drive during respiratory failure. J Appl Physiol 1995;78:1764–1771.lr9, http://www.100md.com
Sassoon CS, Gruer SE, Sieck GC. Temporal relationships of ventilatory failure, pump failure, and diaphragm fatigue. J Appl Physiol 1996;81:238–245.lr9, http://www.100md.com
Davenport PW, Reep RRL. Cerebral cortex and respiration. In: Dempsey JA, Pack AI, editors. Regulation of breathing. New York: Marcel Dekker; 1995. p. 365–388.lr9, http://www.100md.com
Gandevia SC. Spinal and supraspinal factors in human muscle fatigue. Physiol Rev 2001;81:1725–1789.lr9, http://www.100md.com
Scardella AT, Parisi RA, Phair DK, Santiago TV, Edelman NH. The role of endogenous opioids in the ventilatory response to acute flow-resistive loads. Am Rev Respir Dis 1986;133:26–31.
Attali V, Mehiri S, Straus C, Salachas F, Arnulf I, Meininger V, Derenne JP, Similowski T. Influence of neck muscles on mouth pressure response to cervical magnetic stimulation. Am J Respir Crit Care Med 1997;156:509–514.g[impf, 百拇医药
Radell PJ, Eleff SM, Nichols DG. Effects of loaded breathing and hypoxia on diaphragm metabolism as measured by 31P-NMR spectroscopy. J Appl Physiol 2000;88:933–938.g[impf, 百拇医药
Topeli A, Laghi F, Tobin MJ. Can diaphragmatic contractility be assessed by twitch airway pressures in patients with chronic obstructive pulmonary disease? Am J Respir Crit Care Med 1999;160:1369–1374.g[impf, 百拇医药
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Lewis MI, Lorusso TJ, Zhan WZ, Sieck GC. Interactive effects of denervation and malnutrition on diaphragm structure and function. J Appl Physiol 1996;81:2165–2172.zuh%tjy, 百拇医药
Lewis MI, Monn SA, Zhan WZ, Sieck GC. Interactive effects of emphysema and malnutrition on diaphragm structure and function. J Appl Physiol 1994;77:947–955.zuh%tjy, 百拇医药
Aldrich TK, Karpel JP, Uhrlass RM, Sparapani MA, Eramo D, Ferranti R. Weaning from mechanical ventilation: adjunctive use of inspiratory muscle resistive training. Crit Care Med 1989;17:143–147.zuh%tjy, 百拇医药
Johnson PH, Cowley AJ, Kinnear WJ. A randomized controlled trial of inspiratory muscle training in stable chronic heart failure. Eur Heart J 1998;19:1249–1253.zuh%tjy, 百拇医药
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Braun NM, Arora NS, Rochester DF. Respiratory muscle and pulmonary function in polymyositis and other proximal myopathies. Thorax 1983;38:616–623.(Franco Laghi, Steven E. Cattapan, Amal Jubran, Sairam Parthasarathy, Paul Warshawsky, Yoon-Sub A. Ch)
ABSTRACT7wl, http://www.100md.com
TOP7wl, http://www.100md.com
ABSTRACT7wl, http://www.100md.com
INTRODUCTION7wl, http://www.100md.com
METHODS7wl, http://www.100md.com
RESULTS7wl, http://www.100md.com
DISCUSSION7wl, http://www.100md.com
REFERENCES7wl, http://www.100md.com
Because patients who fail a trial of weaning from mechanical ventilation experience a marked increase in respiratory load, we hypothesized that these patients develop diaphragmatic fatigue. Accordingly, we measured twitch transdiaphragmatic pressure using phrenic nerve stimulation in 11 weaning failure and 8 weaning success patients. Measurements were made before and 30 minutes after spontaneous breathing trials that lasted up to 60 minutes. Twitch transdiaphragmatic pressure was 8.9 ± 2.2 cm H2O before the trials and 9.4 ± 2.4 cm H2O after their completion in the weaning failure patients (p = 0.17); the corresponding values in the weaning success patients were 10.3 ± 1.5 and 11.2 ± 1.8 cm H2O (p = 0.18). Despite greater load (p = 0.04) and diaphragmatic effort (p = 0.01), the weaning failure patients did not develop low-frequency fatigue probably because of greater recruitment of rib cage and expiratory muscles (p = 0.004) and because clinical signs of distress mandating the reinstitution of mechanical ventilation arose before the development of fatigue. Twitch pressure revealed considerable diaphragmatic weakness in many weaning failure patients. In conclusion, in contrast to our hypothesis, weaning failure was not accompanied by low-frequency fatigue of the diaphragm, although many weaning failure patients displayed diaphragmatic weakness.
Key Words: ventilator weaning • respiratory muscles • muscle fatigue • phrenic nerve • respiratory insufficiencyii2+j, 百拇医药
INTRODUCTIONii2+j, 百拇医药
TOPii2+j, 百拇医药
ABSTRACTii2+j, 百拇医药
INTRODUCTIONii2+j, 百拇医药
METHODSii2+j, 百拇医药
RESULTSii2+j, 百拇医药
DISCUSSIONii2+j, 百拇医药
REFERENCESii2+j, 百拇医药
When a mechanical load on the respiratory system is too large or continues for too long of a time, the respiratory muscles can develop contractile fatigue (1). In the context of neurophysiology, fatigue represents a decrease in muscle force in response to a given neural stimulus. Contractile fatigue can be short or long lasting. Short-lasting fatigue, also known as high-frequency fatigue, results from accumulation of inorganic phosphate (2), failure of the membrane electrical potential to propagate beyond T tubes (3), and to a lesser extent intramuscular acidosis (4). Long-lasting fatigue (5), also known as low-frequency fatigue, is consistent with the development of and recovery from muscle injury (6, 7), and it can persist for days. Contractile fatigue can be induced in healthy subjects under constrained experimental conditions when subjects willingly continue to generate large subatmospheric swings in intrathoracic pressure irrespective of afferent signals from the respiratory muscles or elsewhere (5, 8, 9).
Patients who fail a trial of weaning from mechanical ventilation are at a considerable risk for developing respiratory muscle fatigue. Much circumstantial evidence suggests that these patients do develop contractile fatigue (10–15). For example, we found that 5 of 17 weaning failure patients experienced an imbalance between mechanical load and respiratory muscle capacity, expressed as a tension–time index (TTdi), which would be expected to induce contractile muscle fatigue (13). None of the experimental techniques used to date, however, provide direct evidence of contractile fatigue, and it is still unknown whether contractile fatigue occurs in patients..e, 百拇医药
The question of whether respiratory muscle fatigue occurs in weaning failure patients is of major clinical importance. Patients who fail a trial of weaning are at a disadvantage when compared with weaning success patients because they have greater abnormalities in lung mechanics (13–15). If these patients also develop contractile fatigue of their respiratory muscles during a failed weaning trial, the superimposed structural injury is likely to set them back in their clinical course. The new injury might even become the ultimate determinant of whether some patients are ever successfully weaned from the ventilator.
The most direct method for detecting fatigue in patients is to stimulate the phrenic nerves and measure the resulting change in transdiaphragmatic pressure. We used this approach to test the hypothesis that patients who fail a trial of weaning from the mechanical ventilation develop contractile fatigue of the diaphragm, whereas successfully weaned patients do not. Some the results of these studies have been previously reported in the form of abstracts (16, 17).jg8u, 百拇医药
METHODSjg8u, 百拇医药
TOPjg8u, 百拇医药
ABSTRACTjg8u, 百拇医药
INTRODUCTIONjg8u, 百拇医药
METHODSjg8u, 百拇医药
RESULTSjg8u, 百拇医药
DISCUSSIONjg8u, 百拇医药
REFERENCESjg8u, 百拇医药
Patientsjg8u, 百拇医药
Nineteen patients whose primary physician considered them ready for weaning were recruited (see online supplement). Appropriate institutional review boards approved the study, and written consents were obtained.
fig.ommitted-?|, http://www.100md.com
TABLE 1. Weaning success-?|, http://www.100md.com
Experimental Setup-?|, http://www.100md.com
Flow and pressure measurements.-?|, http://www.100md.com
Flow and airway, esophageal (Pes), gastric (Pga), and transdiaphragmatic (Pdi) pressures were measured (see online supplement for further details).-?|, http://www.100md.com
Compound diaphragmatic action potentials.-?|, http://www.100md.com
Compound diaphragmatic action potentials were recorded bilaterally using surface electrodes. Single bilateral phrenic nerve stimulation was performed using two magnetic stimulators with two sets of double 40-mm coils that generated a magnetic field of 3.2 Tesla at maximal output (see online supplement for further details).-?|, http://www.100md.com
Protocol-?|, http://www.100md.com
Twitch stimulation before the weaning trial.-?|, http://www.100md.com
To avoid twitch potentiation (5, 18), the patients received controlled ventilation for 20 minutes before delivering the first stimulation. Six to 15 stimulations were then delivered bilaterally at intervals of approximately 15 seconds at end exhalation while closing the inline valve. After the last stimulation, maximal voluntary inspiratory efforts were recorded during a 20-second occlusion of the airway (19) (see online supplement for details).
Trial of spontaneous breathing.+/0, http://www.100md.com
The weaning trial was conducted for up to 1 hour as tolerated. In eight weaning failure and four weaning success patients, arterial blood samples were obtained at 2 minutes and at the end of the trial. Patients who did not develop criteria of weaning failure (13, 20) (see online supplement for criteria) were extubated. Patients who sustained spontaneous breathing for more than 24 hours were deemed the weaning successes group (21). The remaining patients, the weaning failure group, required mechanical ventilation for 3 days to more than 57 days after the study.+/0, http://www.100md.com
Twitch stimulation after the trial.+/0, http://www.100md.com
After the weaning trial, all patients, irrespective of the weaning outcome, were returned to mechanical ventilation for 30 minutes. At the end of this period, twitch Pdi and maximal voluntary inspiratory efforts were measured. To determine whether maximal depolarization of the phrenic nerve was achieved, progressively increasing outputs from the stimulator were delivered in 12 patients (see online supplement for details). Thereafter, patients who had met the a priori criteria of weaning failure were maintained on mechanical ventilation, whereas the remaining patients were extubated.
Twitch interpolation.}j&4[, 百拇医药
Twitch interpolation measurements were performed in seven patients before and after the weaning trial (22) (see online supplement for details).}j&4[, 百拇医药
Physiologic Measurements}j&4[, 百拇医药
Transdiaphragmatic twitch pressure.}j&4[, 百拇医药
Twitch Pdi was measured as the difference between the maximum Pdi displacement secondary to phrenic nerve stimulation and the value immediately before stimulation (18, 23). Criteria for acceptable twitch responses are listed in the online supplement. The within-occasion coefficient of variation of twitch Pdi before and after weaning was 10% or less in 17 patients, and it was within 12 and 14% in the remaining 2 patients. Data collected after the weaning trial did not satisfy the a priori criteria for acceptable twitch responses in 3 of the 19 patients, and they were excluded from data analysis.}j&4[, 百拇医药
Maximum voluntary inspiratory pressure.
The pressure developed by the diaphragm was computed as the maximal excursion in Pdi (Pdimax) during the 20-second occlusions (19).xv@k, http://www.100md.com
Respiratory mechanics and effort indices.xv@k, http://www.100md.com
Inspiratory resistance of the lung, dynamic compliance of the lung, and intrinsic positive end-expiratory pressure (PEEPi) were computed according to standard formulae (24–27). Pressure-time product (PTPdi) and TTdi of the diaphragm were quantified using standard formulae (1, 26–28). The relative contribution of the different respiratory muscles to tidal breathing was assessed as the ratio of swings in Pga to swings in Pes (Pga/Pes) (see online supplement for calculation of these variables).xv@k, http://www.100md.com
Data Analysisxv@k, http://www.100md.com
Analysis of variance and t tests were used as needed (see online supplement). Some measurements are included in another manuscript (29).xv@k, http://www.100md.com
RESULTSxv@k, http://www.100md.com
TOP
ABSTRACTa9swzq., http://www.100md.com
INTRODUCTIONa9swzq., http://www.100md.com
METHODSa9swzq., http://www.100md.com
RESULTSa9swzq., http://www.100md.com
DISCUSSIONa9swzq., http://www.100md.com
REFERENCESa9swzq., http://www.100md.com
Nine patients met the a priori criteria for weaning failure after 44 ± 7 minutes of spontaneous breathing, and mechanical ventilation was reinstituted. Seven patients tolerated a trial of 60 minutes without distress and were extubated.a9swzq., http://www.100md.com
At the beginning of the weaning trial, PaO2, PaCO2, and pH were not different between the groups . By the end of the trial, a small decrease in pH (p = 0.025) occurred in the failure group, and no significant change occurred in the success group.a9swzq., http://www.100md.com
fig.ommitteda9swzq., http://www.100md.com
TABLE 2. Alterations in arterial blood gas measurementsa9swzq., http://www.100md.com
Twitch and Maximal Inspiratory Pressuresa9swzq., http://www.100md.com
Magnetic stimulation elicited twitch pressures in all patients . Before the weaning trial, twitch Pdi was 8.9 ± 2.2 cm H2O in the failure group and 10.3 ± 1.5 cm H2O in the success group (p = 0.63) . After the trial, twitch Pdi was 9.4 ± 2.4 in the failure group and 11.2 ± 1.8 cm H2O in the success group (p = 0.58); these values were not different from the values for each group before the trial. (In the failure patient who had a malfunctioning gastric balloon, twitch Pes was -20.6 ± 0.6 cm H2O before and -18.2 ± 0.6 cm H2O after the trial.) Before the trial, Pdimax was 39.4 ± 6.6 cm H2O in the failure group and 55.2 ± 8.2 cm H2O in the success group (p = 0.36) . The values of Pdimax at 30 minutes after the trial were 41.0 ± 6.8 cm H2O in the failure group and 53.5 ± 8.3 cm H2O in the success group (p = 0.26); these values were not different from the values for each group before the trial.
fig.ommittedor\ot), 百拇医药
Figure 1. Pes, Pga, Pdi, and compound motor action potentials (CAMP) of the right and left hemidiaphragms after phrenic nerve stimulation before (left) and after (right) a failed trial of weaning. The end-expiratory value of Pes and the amplitude of the right and left CAMPs were the same before and after the trial, indicating that the stimulations were delivered at the same lung volume and that the stimulations achieved the same extent of diaphragmatic recruitment. The amplitude of twitch Pdi elicited by phrenic nerve stimulation was the same before and after weaning.or\ot), 百拇医药
fig.ommittedor\ot), 百拇医药
Figure 2. Transdiaphragmatic twitch pressure (twitch Pdi), recorded before and 30 minutes after a weaning trial in nine weaning failure patients (closed symbols, left panel) and seven weaning success patients (open symbols, right panel). Twitch Pdi did not differ between the groups before the trial, and it did not decrease after the trial in either group. Bars represent group mean ± SE.or\ot), 百拇医药
fig.ommittedor\ot), 百拇医药
Figure 3. Pdimax, recorded before and 30 minutes after a weaning trial, in nine weaning failure patients (closed symbols, left) and seven weaning success patients (open symbols, right). Pdimax did not differ between the groups before the trial, and it did not decrease after the trial in either group. Bars represent group mean ± SE.
Among the seven patients in whom twitch interpolation was performed, the amplitude of the compound diaphragmatic action potential during interpolation was less than that during passive conditions. A detectable superimposed twitch, however, was always present—even in those four patients in whom it was possible to time the superimposed stimulus at, or near to, Pdimax . This observation suggests that the phrenic nerve was not maximally stimulated by a "maximal" voluntary maneuver.m6@31, 百拇医药
fig.ommittedm6@31, 百拇医药
Figure 4. Continuous recordings of Pes, Pga, and Pdi during airway occlusion in a patient after a failed trial of weaning. Phrenic nerve stimulation (arrow) during the maximal inspiratory effort resulted in a detectable superimposed twitch. The presence of a superimposed twitch during a maximal effort indicates that voluntary activation of the diaphragm was incomplete.m6@31, 百拇医药
Diaphragmatic Pressure Output (PTPdi) and TTdim6@31, 百拇医药
At trial onset, PTPdi/min was 337 ± 51 cm H2O x seconds/minute in the failure group and 205 ± 27 cm H2O x seconds/minute in the success group . At the end of the trial, PTPdi/min increased to 523 ± 130 cm H2O x seconds/minute in the failure group (p < 0.05) and to 367 ± 64 cm H2O x seconds/minute in the success group (p < 0.01). Over the course of the trial, PTPdi/min did not differ between the two groups (p = 0.18).
fig.ommittedhm:m, 百拇医药
Figure 5. PTPdi (left panel) and TTdi of the diaphragm (right panel) during a weaning trial in the failure (closed symbols) and success (open symbols) groups. Between the onset and the end of the trial, increases in PTPdi (p < 0.005) and TTdi (p < 0.005) occurred in both groups. Over the course of the trial, the failure group had higher values of TTdi (p = 0.01) but not of PTPdi (p = 0.18) than did the success group. Bars represent SE.hm:m, 百拇医药
Over the course of the trial, TTdi was higher in the failure group than in the success group (p = 0.01) . Of the nine failure patients, seven had a TTdi at or above 0.15 (the putative threshold for task failure and fatigue) during two or more isotimes. Of the seven success patients, only one had a TTdi at or above 0.15 during two isotimes.hm:m, 百拇医药
Ribcage and Expiratory Muscle Recruitmenthm:m, 百拇医药
At trial onset, the Pga/Pes ratio was greater in the failure group than in the success group: -0.03 ± 0.04 versus -0.19 ± 0.05 (p = 0.002)
. Over the course of the trial, Pga/Pes remained greater in weaning failure patients (p = 0.004). At the end of the trial, the ratio had increased to 0.12 ± 0.07 in the failure group (p = 0.05). At the end of the trial, the ratio in the success group was -0.10 ± 0.02. Because patients with diaphragmatic paralysis can have enhanced rib cage muscle recruitment even in the absence of respiratory distress (30), Pga/Pes ratio of the failure patients was compared with that of the success patients after excluding the two patients (both weaning failure patients) with hemidiaphragmatic paralysis. The Pga/Pes was still greater in the weaning failure patients (p = 0.01)—a finding similar to the overall group.)c@5{:, http://www.100md.com
fig.ommitted)c@5{:, http://www.100md.com
Figure 6. Pga/Pes—an index of rib cage and expiratory muscle contribution to respiratory effort—during a weaning trial in the failure (closed symbol) and success (open symbol) groups. Between the onset and the end of the trial, Pga/Pes increased in the failure (p = 0.04) and success groups (p = 0.05), and the ratio was higher in the failure group than in the success group over the course of the trial (p = 0.004). Bars represent SE.
Respiratory Mechanics6;3up, 百拇医药
At onset of the trial, inspiratory resistance of the lung was not different between the failure and success groups: 12.8 ± 1.8 versus 10.4 ± 0.6 cm H2O/L/second (p = 0.44). During the course of the trial, inspiratory resistance of the lung in the failure group became greater than in the success group (p = 0.05) (data not shown). At trial onset, dynamic compliance of the lung was 55 ± 11 ml/cm H2O in the failure group and 184 ± 81 ml/cm H2O in the success group. During the course of the trial, dynamic lung compliance was lower in the failure group than that in the success group (p = 0.042) (data not shown).6;3up, 百拇医药
At onset of the trial, total PEEPi (not corrected for expiratory rise in Pga) was not different between the failure and success groups: 4.6 ± 1.3 versus 2.1 ± 0.4 cm H2O (p = 0.13). Likewise, corrected PEEPi (corrected for expiratory rise in Pga) was not different between the failure and success groups: 3.8 ± 1.2 versus 2.1 ± 0.4 cm H2O (p = 0.59). At the end of the trial, total PEEPi had increased to 11.6 ± 4.4 cm H2O (p = 0.03) in the failure group and to 4.4 ± 1.0 cm H2O (p = 0.001) in the success group. At the end of the trial, corrected PEEPi was 6.2 ± 3.6 cm H2O in the failure group. The values of total and corrected PEEPi in the success patients were nearly identical.
DISCUSSION17h4^, 百拇医药
TOP17h4^, 百拇医药
ABSTRACT17h4^, 百拇医药
INTRODUCTION17h4^, 百拇医药
METHODS17h4^, 百拇医药
RESULTS17h4^, 百拇医药
DISCUSSION17h4^, 百拇医药
REFERENCES17h4^, 百拇医药
This is the first report of systematic measurements of the contractile response of the diaphragm to phrenic nerve stimulation in patients being weaned from mechanical ventilation. We found that patients failing a weaning trial did not develop low-frequency fatigue.17h4^, 百拇医药
Researchers have long thought that some, if not most, patients who fail a weaning trial develop respiratory muscle fatigue (10, 12–15). The techniques used in previous studies were indirect (10–14), raising doubt as to whether fatigue truly occurred (31). We used a direct test of muscle fatigability, namely stimulation of the phrenic nerve and measurement of the resulting Pdi (32, 33). Even with this technique, data can be inaccurate because of several confounding variables: changes in lung volume, variation in the degree of neural depolarization achieved by the stimulator, and the contraction history of the muscle (i.e., twitch potentiation). We took particular care to avoid these confounding factors and excluded data that did not satisfy our a priori inclusion criteria. As such, we view the absence of a fall in twitch Pdi as evidence that low-frequency fatigue is not a mechanism of weaning failure.
Factors That Can Contribute to Fatigue{nv$et, 百拇医药
Diaphragmatic fatigue occurs only when there is a critical stress on the muscle. A critical stress can result from an increase in mechanical load, which leads to an increase in respiratory center output and thus increase in respiratory muscle pressure (PTPdi). When a patient's muscle strength is small, an increase in PTPdi is more likely to exceed the diaphragmatic threshold (TTdi) for fatigue (1).{nv$et, 百拇医药
At onset of the weaning trial, the weaning failure patients had abnormalities in lung mechanics comparable to those reported in previous studies: inspiratory resistance of the lung was 13 cm H2O/L/second versus 9 (13) and 22 cm H2O/L/second (14); dynamic lung compliance was 55 ml/cm H2O versus 48 (13) and 70 ml/cm H2O (14), and total PEEPi was 4.6 cm H2O versus 2.0 (13) and 5.9 cm H2O (14). By the end of the trial, inspiratory resistance of the lung (17 cm H2O/L/second) and total PEEPi (12 cm H2O) increased to or exceeded previously reported values (16 cm H2O/L/second and 4 cm H2O, respectively [13]). Dynamic lung compliance at the end of a failed trial was within the range of previously reported values: 48 ml/cm H2O versus 29 (13) and approximately 70 ml/cm H2O (14). Accordingly, our weaning failure patients displayed abnormalities in pulmonary mechanics equivalent to patients in previous studies. Our weaning failure patients displayed greater resistive and elastic loads than did our weaning success patients—a finding similar to our previous report (13).
The increase in PTPdi over the course of the weaning trial indicates that the respiratory centers attempted to defend alveolar ventilation in the face of deteriorating lung mechanics. This finding is consistent with our previous report of an increase in overall respiratory muscle pressure (esophageal pressure-time product [PTPe]) (13). In that previous study (13), the increase in PTPes was not sufficient to prevent hypercapnia in 13 of the 17 weaning failure patients. Hypercapnia was less common in this study: PaCO2 increased by 5 to 16 percent in three of eight weaning failure patients in whom arterial blood samples where obtained. Three factors may account for the difference in the two studies: baseline arterial samples were collected at approximately 2 minutes after the start of spontaneous breathing in this study, whereas they were collected during controlled mechanical ventilation in the previous study; only four weaning failure patients in this study had COPD as compared with all patients in the previous study, and respiratory muscle effort, as reflected by PTPes, was somewhat greater in this study than in the previous study (538 and 388 cm H2O x seconds/minute, respectively).
TTdi combines three key determinants of diaphragmatic fatigue: pressure generated by the diaphragm (PTPdi), muscle strength (Pdimax), and respiratory duty cycle (inspiratory time/total respiratory cycle time). In healthy subjects, a sustained increase in TTdi above 0.15 leads to diaphragmatic fatigue (1). The threshold of 0.15 was exceeded by 77% of our weaning failure patients and by 15% of our weaning success patients. However, no patient showed evidence of low-frequency fatigue. Three factors could explain why a high TTdi was not accompanied by fatigue: the heightened muscle effort was not sustained for a sufficient time; endurance of the diaphragm was greater in weaning failure patients than in healthy subjects; and the recorded value of TTdi was an overestimate.&|, http://www.100md.com
Bellemare and Grassino (1) reported that the relationship between TTdi and time to task failure in healthy subjects follows an inverse power function: time to task failure = 0.1 (TTdi)-3.6. The average duration of weaning trials in our failure patients was 44 minutes. The average values of TTdi for the first, second, third, and fourth quintiles of the trial durations were 0.17, 0.17, 0.22, and 0.22, respectively. Based on the formula of Bellemare and Grassino (1), the expected times to task failure for the respective quintiles would be 59, 59, 28, and 28 minutes. The average value of TTdi during the last minute of the trial was 0.26, and the weaning failure patients would be predicted to sustain this effort for another 13 minutes before developing task failure. These calculations suggest that weaning failure patients did not sustain the increase in load for a duration sufficient to cause low-frequency fatigue; that is, the trial was stopped because patients developed a priori–defined clinical manifestations of respiratory distress before they developed fatigue.
Fatigue is not an all-or-none phenomenon (34). Measuring twitch pressures after forceful voluntary contractions, so-called potentiated twitches, has been suggested as a means for detecting an early decrease in muscle contractility (34, 35). In eight patients (four weaning failure and four weaning success patients), we were able to record the potentiated twitches both before and after weaning by stimulating the phrenic nerves immediately after the patients performed maximal voluntary inspiratory efforts. Potentiated twitch Pdi was 8.6 ± 3.1 cm H2O before the trial and 8.7 ± 2.9 cm H2O after the trial in the four weaning failure patients; the corresponding values for nonpotentiated twitches were 6.9 ± 2.6 and 6.8 ± 2.4 cm H2O, respectively. Potentiated twitch Pdi was 10.5 ± 1.5 cm H2O before the trial and 10.6 ± 1.1 cm H2O after the trial in the four weaning success patients; the corresponding values for nonpotentiated twitches were 8.3 ± 1.5 and 8.7 ± 1.4 cm H2O, respectively. The failure of potentiated twitch Pdi to decrease after a failed weaning trial further supports our reasoning that the inspiratory load, even if it was in the fatiguing range, was not sustained for a sufficient length of time to cause fatigue.
If endurance of the respiratory muscles is supranormal in critically ill patients, fatigue would not develop at a TTdi of 0.15. Direct measurements of diaphragmatic endurance have not been obtained in critically ill patients, but circumstantial evidence suggests that it is not supranormal. Indeed, endurance of the diaphragm is decreased in stable patients with spinal cord injury (36), probably because fatigue-sensitive, type II myosin heavy chains are increased in the diaphragm (37).0s/, http://www.100md.com
Reliable calculation of TTdi is critically dependent on an accurate measurement of diaphragmatic strength. Our data show that even carefully made measurements of Pdimax commonly underestimate maximum strength. The pressure tracings in all of our patients during the Pdimax measurements had the characteristics of a Mueller maneuver: large negative excursions in Paw and Pes with slightly positive (or, in one patient, negative) deflections in Pga . In healthy subjects, the combination of a Mueller maneuver with an expulsive maneuver results in higher values of Pdimax (38), but critically ill patients have great difficulty in performing the combined maneuver. Moreover, the finding of twitch interpolation (that is, a measurable twitch Pdi when the phrenic nerves were stimulated during maximum voluntary effort) indicates that patients were not able to activate completely the diaphragm during a "maximum" maneuver (22) . The underestimation of Pdimax will necessarily produce an overestimate of TTdi, which further explains why patients did not develop low-frequency fatigue despite recorded values of TTdi above 0.15.
Defense Mechanisms against Low-Frequency Fatigue', http://www.100md.com
All of the weaning failure patients experienced severe respiratory distress, but none developed low-frequency fatigue. Three strategies may have protected the diaphragm against fatigue: increased rib cage and expiratory muscle recruitment, the early reinstitution of mechanical ventilation, and respiratory center downregulation.', http://www.100md.com
Immediately after the start of the weaning trial, the weaning failure patients displayed greater recruitment of rib cage and expiratory muscles during tidal breathing than did the weaning success patients (greater Pga/Pes) (Figure 6). (Excluding the two patients with hemidiaphragmatic paralysis does not affect this finding.) The same alteration in respiratory muscle recruitment has also been reported in patients (39–42) and volunteers (34, 43) when diaphragmatic effort is increased during tidal breathing. Recruitment of the rib cage and expiratory muscles appears to contribute to the development of dyspnea (41, 44). Clinicians also take increased activity of the rib cage and abdominal muscles into account in deciding whether to continue or interrupt a weaning trial.
The increase in PTPdi during the weaning trial signifies a progressive increase in respiratory motor output, as has been previously reported (14, 45, 46). Some patients, however, developed hypercapnia, suggesting that respiratory motor output may have been downregulated. Studies in animals show that a decrease in respiratory motor output occurs as a preterminal event (47) and a decrease in drive can be accompanied by the development of diaphragmatic fatigue at the time of apnea (48). Afferent signals originating in fatiguing muscles may activate neural pathways responsible for downregulation of respiratory motor output (49–52). Downregulation of respiratory drive will decrease metabolic demands and the likelihood of contractile fatigue (53). During the usual protocol for inducing respiratory muscle fatigue in healthy volunteers (achieving a target inspiratory pressure while breathing through a resistor [1, 5, 9]), the exhortation of the investigators and the volition of the subjects may override the afferent signals that downregulate respiratory drive (9). The artificial and constrained nature of this laboratory protocol is very different from the natural evolution of respiratory distress in weaning failure patients.
Other Causes of Weaning Failure9ikv};q, 百拇医药
Although low-frequency fatigue does not appear to be responsible for weaning failure, other abnormalities of the respiratory muscles may be causative. Possible mechanisms include diaphragmatic weakness, atrophy, high-frequency fatigue, and hyperinflation.9ikv};q, 百拇医药
In our laboratory, the mean amplitude of nonpotentiated twitch Pdi ranges from 35.4 to 38.9 cm H2O in healthy subjects (5, 23, 34) and from 17.2 to 20.1 cm H2O in stable patients with COPD (54, 41). Most of our weaning failure and weaning success patients had twitch Pdi values lower than the values recorded in ambulatory patients. Six weaning failure patients had twitch Pdi values of less than 10 cm H2O. These results suggest that many mechanically ventilated patients have diaphragmatic weakness and that some weaning failure patients have severe weakness.9ikv};q, 百拇医药
Eight weaning failure patients and six weaning success patients had infections (pneumonia or sepsis) while receiving ventilator support. Sepsis is known to cause diaphragmatic injury and weakness (55, 56). All of our patients had been ventilated with patient-triggered modes, and the involved muscle contractions may aggravate the diaphragmatic injury caused by sepsis (57). Several studies in experimental animals (58) demonstrate that mechanical ventilation can induce respiratory muscle atrophy, although it is not known whether this occurs in patients. Many ventilator-supported patients are malnourished (59), and this will further contribute to atrophy (60–62).
Our study does not directly address whether the patients developed high-frequency fatigue, as has been suggested (11). The lack of change in twitch Pdi and Pdimax does not exclude the possibility. High-frequency fatigue can resolve within 10 to 15 minutes (4, 53), and it could have disappeared by the time of testing (30 minutes after the end of the weaning trial).z(, 百拇医药
Weakness of the inspiratory muscles arises when patients develop progressive hyperinflation. An increase in end-expiratory volume causes shortening of inspiratory muscles and a decrease in force generation. Total PEEPi increased over the course of the trial in the weaning failure patients, but an indirect measurement of end-expiratory volume—PEEPi corrected for expiratory muscle recruitment (26)—revealed no change. Corrected PEEPi was also not different between weaning success and weaning failure patients, suggesting that hyperinflation did not increase during the trials.z(, 百拇医药
Clinical Implications
Respiratory muscle fatigue has been thought to be a common cause of weaning failure, and accordingly, clinical management has been directed toward improving the capacity of the respiratory muscles to generate (strength) and to sustain (endurance) force (63). Does the lack of low-frequency fatigue in our weaning failure patients mean that these strategies are misdirected? No. Many weaning failure patients have severe diaphragmatic weakness (66% had twitch Pdi values below 10 cm H2O), and weakness probably sets in motion the complex processes described in this study, which ultimately lead to the early reinstitution of mechanical ventilation.3, http://www.100md.com
Investigators have shown that respiratory muscle training can increase respiratory muscle strength and endurance in ambulatory patients, but the improvement has not been shown to achieve better clinical well-being or outcome (64, 65). The lack of benefit is not surprising because baseline maximum inspiratory pressure was not reduced to a level that hinders spontaneous breathing (66). In weaning failure patients, however, a small improvement in respiratory muscle strength and endurance could have a profound effect on clinical outcome. Based on the results of this study, it could prove useful to develop a training regimen that can achieve an improvement in twitch pressure (the noninvasive measurement of twitch airway pressure may satisfactorily substitute for twitch Pdi [29]). Such a training regimen could have a major benefit in the difficult-to-wean patients (63), although proof of this possibility requires a randomized control trial. Although the challenge of designing and undertaking such a trial will be considerable, the scientific motivation for such a study is stronger than before.
In summary, patients who fail a weaning trial displayed greater mechanical load than did weaning success patients. The increase in load caused TTdi to increase above the threshold associated with fatigue, yet twitch Pdi and Pdimax did not decrease in these patients. Factors that may have protected the diaphragm against fatigue include greater rib cage and expiratory muscle recruitment, downregulation of respiratory motor output, and early reinstitution of mechanical ventilation. In conclusion, in contrast to our hypothesis, weaning failure was not accompanied by low-frequency fatigue of the diaphragm, although many weaning failure patients displayed severe diaphragmatic weakness.[6q{'f, http://www.100md.com
REFERENCES[6q{'f, http://www.100md.com
TOP[6q{'f, http://www.100md.com
ABSTRACT[6q{'f, http://www.100md.com
INTRODUCTION[6q{'f, http://www.100md.com
METHODS[6q{'f, http://www.100md.com
RESULTS[6q{'f, http://www.100md.com
DISCUSSION[6q{'f, http://www.100md.com
REFERENCES[6q{'f, http://www.100md.com
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