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ATS/ERS Statement on Respiratory Muscle Testing

	INTRODUCTION

TOP INTRODUCTION Introduction 1. Tests of Overall... REFERENCES 2. Tests of Respiratory... REFERENCES  3. Electrophysiologic Techniques... REFERENCES   4. Tests of Respiratory... REFERENCES    5. Assessment of Respiratory... REFERENCES     6. Assessment of Chest... REFERENCES     8. Tests of Upper... REFERENCES     9. Tests of Respiratory... REFERENCES     10. Assessment of Respiratory... REFERENCES

Introduction, 520

1. Tests of Overall Respiratory Function

G. John Gibson, William Whitelaw, Nikolaos Siafakas

Static Lung Volumes, 521

Dynamic Spirometry and Maximum Flow, 521

Maximum Voluntary Ventilation, 522

Arterial Blood Gases: Awake, 522

Measurements during Sleep, 523

Tests of Respiratory Control, 524

Carbon Monoxide Transfer, 525

Exercise Testing, 526

Conclusion, 526

2. Tests of Respiratory Muscle Strength

Malcolm Green, Jeremy Road, Gary C. Sieck, Thomas Similowski

Pressure Measurements, 528

Devices for Measuring Pressures, 528

Techniques for Pressure Measurement, 530

Volitional Tests of Respiratory Muscle Strength, 531

Pressures Obtained via Phrenic Nerve Stimulation, 535

Abdominal Muscle Stimulation, 542

Conclusion, 542

3. Electrophysiologic Techniques for the Assessment of Respiratory Muscle Function

Thomas K. Aldrich, Christer Sinderby, David K. McKenzie, Marc Estenne, Simon C. Gandevia

Electromyography, 548

Stimulation Tests, 554

Conclusion, 556

Summary, 557

4. Tests of Respiratory Muscle Endurance

Thomas Clanton, Peter M. Calverly, Bartolome R. Celli

Measures of Respiratory Muscle Activity Used in Endurance Testing, 559

Ventilatory Endurance Tests, 562

Endurance to External Loads, 564

Endurance of the Diaphragm, 568

Conclusion, 569

5. Assessment of Respiratory Muscle Fatigue

Gerald S. Supinski, Jean Will Fitting, François Bellemare

Types of Fatigue, 571

Tests of Respiratory Muscle Fatigue, 572

Conclusion, 578

6. Assessment of Chest Wall Function

Stephen H. Loring, Andre de Troyer, Alex E. Grassino

Pressures in the Chest Wall, 580

Assessment of the Properties of the Relaxed Human Chest Wall: Rahn Diagram, 580

Assessment of the Function of the Active Chest Wall: Campbell Diagram, 581

Estimation of Ventilation Based on Chest Wall Motion: Konno-Mead Diagram, 582

Devices Used to Monitor Breathing: Pneumograph, Magnetometer, and Respiratory Inductive Plethysmograph, 583

Optical Devices Used to Measure Chest Wall Motion, 584

Inferring Respiratory Muscle Contribution to Breathing from Chest Wall Motion, 584

Inferring Respiratory Muscle Contribution to Breathing from the Esophageal–Gastric Pressure Relationship: Macklem Diagram, 585

Inferring Respiratory Muscle Contribution to Breathing from Pressure–Volume Relationships, 585

Inferring Diaphragm Activation and Electromechanical Effectiveness from EMG, 585

Conclusion, 586

7. Imaging Respiratory Muscle Function

Neil B. Pride, Joseph R. Rodarte

Transmission Radiography, 588

Ultrasound, 589

Volumetric Imaging, 591

Nuclear Medicine, 591

Summary, 591

8. Tests of Upper Airway Function

Neil J. Douglas, Samuel T. Kuna

Electromyography, 593

Upper Airway Resistance, 594

Indirect Laryngoscopy, 596

Fiberoptic Imaging, 596

Computed Tomographic Scanning, 596

Magnetic Resonance Imaging, 597

Acoustic Reflection, 597

Flow–Volume Loops, 597

Polysomnography, 597

Muscle Biopsy, 598

Strength, Fatigue, and Endurance of Upper Airway Muscles, 598

Site of Pharyngeal Airway Closure during Sleep, 598

Conclusion, 598

9. Tests of Respiratory Muscle Function in Children

Claude Gaultier, Julian Allen, Sandra England

Physiology of the Developing Respiratory Pump, 601

Tests of Respiratory Function, 601

Conclusion, 607

10. Assessment of Respiratory Muscle Function in the Intensive Care Unit

Martin J. Tobin, Laurent Brochard, Andrea Rossi

Breathing Pattern, 610

Lung Volumes, 611

Pressure Measurements, 611

Prediction of Weaning, 617

Conclusion, 619

	INTRODUCTION

TOP INTRODUCTION Introduction 1. Tests of Overall... REFERENCES 2. Tests of Respiratory... REFERENCES  3. Electrophysiologic Techniques... REFERENCES   4. Tests of Respiratory... REFERENCES    5. Assessment of Respiratory... REFERENCES     6. Assessment of Chest... REFERENCES     8. Tests of Upper... REFERENCES     9. Tests of Respiratory... REFERENCES     10. Assessment of Respiratory... REFERENCES

This official joint statement represents the work of an expert ATS/ERS committee, which reviewed the merits of currently known techniques available to evaluate respiratory muscle function. The statement consists of 10 sections, each addressing a major aspect of muscle function or a particular field of application. Each section addresses the rationale for the techniques, their scientific basis, the equipment required, and, when pertinent, provides values obtained in healthy subjects or in patients. Some of the techniques reviewed in this statement have thus far been used primarily in clinical research and their full potential has not yet been established; however, they are mentioned for the purpose of stimulating their further development.

Through continued efforts in the area of respiratory muscle testing, it is anticipated that there will be further enhancement of diagnostic and treatment capabilities in specialties such as intensive care, sleep medicine, pediatrics, neurology, rehabilitation, sports medicine, speech therapy, and respiratory medicine.

	1. Tests of Overall Respiratory Function

TOP INTRODUCTION Introduction 1. Tests of Overall... REFERENCES 2. Tests of Respiratory... REFERENCES  3. Electrophysiologic Techniques... REFERENCES   4. Tests of Respiratory... REFERENCES    5. Assessment of Respiratory... REFERENCES     6. Assessment of Chest... REFERENCES     8. Tests of Upper... REFERENCES     9. Tests of Respiratory... REFERENCES     10. Assessment of Respiratory... REFERENCES

STATIC LUNG VOLUMES
Rationale and Scientific Basis
The most frequently noted abnormality of lung volumes in patients with respiratory muscle weakness is a reduction in vital capacity (VC). The pattern of abnormality of other subdivisions of lung volume is less consistent. Residual volume (RV) is usually normal or increased, the latter particularly with marked expiratory weakness (1). Consequently, total lung capacity (TLC) is less markedly reduced than VC, and the RV/TLC and FRC/TLC ratios are often increased without necessarily implying airway obstruction.

The VC is limited by weakness of both the inspiratory muscles, preventing full inflation, and expiratory muscles, inhibiting full expiration. In addition to the direct effect of loss of muscle force, reductions in compliance of both the lungs (2) and chest wall (3) also contribute to the reduction of VC in patients with chronic respiratory muscle weakness. In severe weakness, the TLC and VC relate more closely to lung compliance than to the distending force (4, 5) (Figure 1) . The mechanism of reduced lung compliance is unclear. Contrary to earlier suggestions, it is probably not simply due to widespread microatelectasis (6). Static lung volumes may also be affected in some patients by coexistent lung or airway disease. Vital capacity, thus, reflects the combined effect of weakness and the static mechanical load on the respiratory muscles.

View larger version (18K): [in this window] [in a new window]   Figure 1. Relation between static lung compliance and total lung capacity in 25 patients with chronic respiratory muscle weakness of varying severity. Dashed line is regression line. Reprinted by permission from Reference 5.

View larger version (23K): [in this window] [in a new window]   Figure 2. Curvilinear relation of maximum static inspiratory pressure (inspiratory muscle strength) to vital capacity in 25 patients with chronic weakness of varying severity. Dashed line and statistics relate to logarithmic regression. Solid line represents relationship calculated from a standard maximal static pressure–volume diagram assuming normal elastic properties of the respiratory system. The greater than expected reduction in VC is due to reduced compliance of the lungs and chest wall. Reprinted by permission from Reference 5.

Methodology and Equipment
Recommendations and requirements for the measurement of VC and other lung volumes are covered in detail elsewhere (9, 10).

Advantages
VC has excellent standardization, high reproducibility and well-established reference values. It is easily performed, widely available, and economical. It is quite sensitive for assessing progress in moderate to severe respiratory muscle weakness. The rate of decline has been shown to predict survival in both amyotrophic lateral sclerosis (11) and Duchenne muscular dystrophy (12).

Disadvantages
VC has poor specificity for the diagnosis of respiratory muscle weakness. In mild weakness, it is generally less sensitive to changes than are maximum pressures (13).

Applications
Serial measurements of VC should be routine in monitoring progress of patients with acute and chronic respiratory muscle weakness.

Measurement of postural change of VC gives a simple index of weakness of the diaphragm relative to the other inspiratory muscles.

DYNAMIC SPIROMETRY AND MAXIMUM FLOW
Rationale and Scientific Basis
Airway resistance is normal in uncomplicated respiratory muscle weakness (14). Airway function may appear to be supernormal when volume-corrected indices such as FEV₁/VC or specific airway conductance are used (2).

The maximum expiratory and maximum inspiratory flow–volume curves characteristically show a reduction in those flows that are most effort dependent, that is, maximum expiratory flow at large lung volumes (including peak expiratory flow) and maximum inspiratory flow at all lung volumes (2, 5) (Figure 3) . The descending limb of the maximum expiratory flow–volume curve may suggest supernormal expiratory flow when this is related to absolute volume (2, 3). With severe expiratory weakness, an abrupt fall in maximum expiratory flow is seen immediately before RV is reached (1). In health the FEV₁ is usually less than the forced inspiratory volume in 1 second. Reversal of this ratio is seen with upper (extrathoracic) airway obstruction, as well as in respiratory muscle weakness, and may give a pointer to these diagnoses during routine testing.

View larger version (15K): [in this window] [in a new window]   Figure 3. Schematic maximum expiratory and inspiratory flow–volume curves in a patient with severe respiratory muscle weakness (solid line) compared with predicted (dotted line). Volume is expressed in absolute terms (i.e., percent predicted). Note marked reductions in FVC, V·Emax at higher volumes, and V·Imax at all volumes. Note also the blunted contour of the expiratory curve and the abrupt cessation of V·Emax at RV. In the midvolume range, V·Emax exceeds that predicted for the absolute lung volume.

Oscillations of maximum expiratory and/or inspiratory flow—the so-called sawtooth appearance—are seen particularly when the upper airway muscles are weak and in patients with extrapyramidal disorders (17) (Figure 4) .

View larger version (13K): [in this window] [in a new window]   Figure 4. Maximum expiratory and inspiratory flow–volume curves, showing "sawtooth" oscillations of flow.

Advantages
Maximum flow–volume curves are easily performed, widely available, and economical. Peak expiratory flow can be obtained with simple portable devices.

Disadvantages
Intersubject variability is greater than for VC. Reference values for _V^·Emax at standard percentages of FVC may present problems of interpretation.

Applications
Visual inspection may suggest the likelihood of weakness.

The sawtooth appearance in an appropriate context may suggest weakness or dyscoordination of upper airway muscles. However, this appearance is nonspecific and is seen also in some subjects with obstructive sleep apnea, nonapneic snoring, and thermal injury of the upper airway.

MAXIMUM VOLUNTARY VENTILATION
Rationale and Scientific Basis
The maximum voluntary ventilation was formerly recommended as a more specific test for muscle weakness than volume measurements but, in practice, the proportionate reduction is usually similar to that of VC (18, 19). Disproportionate reductions may be seen in Parkinson's disease (20), in which the ability to perform frequent alternating movements is impaired.

Methodology and Equipment
Recommendations and requirements are covered elsewhere (10).

Advantages
No advantages are perceived in most situations.

Disadvantages
The test depends on motivation and is tiring for the subject.

Applications
Maximum voluntary ventilation is not generally recommended for patients with known or suspected respiratory muscle weakness but may be helpful in the assessment and monitoring of patients with extrapyramidal disorders.

ARTERIAL BLOOD GASES: AWAKE
Rationale and Scientific Basis
In chronic muscle weakness, even when quite severe, Pa_O2 and the alveolar–arterial PO₂ difference are usually only mildly abnormal (2, 21). In acute muscle weakness, Pa_O2 may be more markedly reduced, but the picture may be complicated by atelectasis or respiratory infection (22).

With mild weakness, Pa_CO2 is usually less than normal (19, 22), implying alveolar hyperventilation. In the absence of primary pulmonary disease, daytime hypercapnia is unlikely unless respiratory muscle strength is reduced to < 40% of predicted and VC is reduced to < 50% of predicted (19) (Figures 5 and 6) . Elevation of venous bicarbonate concentration occasionally gives an important clue to otherwise unsuspected hypercapnia. Patients with muscle weakness are less able than normal subjects to compensate for minor changes in respiratory function. If hypercapnia is established or incipient, even minor infections may cause a further rise in Pa_CO2, as also may injudicious use of sedative drugs or uncontrolled oxygen.

View larger version (16K): [in this window] [in a new window]   Figure 5. Relation of daytime PaCO2 to "respiratory muscle strength" (RMS = arithmetic mean of PImax and PEmax) in 33 patients with "uncomplicated" chronic myopathy (closed circles, regression lines) and 14 patients with myopathy plus chronic lung disease (open circles). Note that in uncomplicated myopathy, PaCO2 is reduced (< 40 mm Hg) in most patients with mild weakness and is likely to be elevated only when RMS < 40% predicted. Reprinted by permission from Reference 19.

View larger version (16K): [in this window] [in a new window]   Figure 6. Relation of daytime PaCO2 to VC in 37 patients with uncomplicated chronic myopathy (closed circles, regression line) and 16 with myopathy plus chronic lung disease (open circles). Reprinted by permission from Reference 19.

Disadvantages
Definitely abnormal arterial blood gases usually imply late and severe impairment of respiratory muscles and therefore their measurement is neither sensitive nor specific. Daytime values may underestimate the severity of abnormal gas exchange.

Applications
Measurement of arterial blood gases is routinely performed to assess the consequences of respiratory muscle weakness.

MEASUREMENTS DURING SLEEP
Rationale and Scientific Basis
Patients with moderate or severe respiratory muscle weakness characteristically show dips in oxygen saturation (Sa_O2) related to periods of rapid eye movement (REM) sleep (23, 24) (Figure 7) . The episodic desaturation is usually due to hypopnea and less often to apnea and is associated particularly with phasic REM sleep, when brief periods of rapid, irregular eye movements are accompanied by reduced activity of skeletal muscles (24) (Figure 8) . The hypopneas and/or apneas may appear to be either "central" (Figure 8) or "obstructive," or sometimes a mixture of both. The precise pattern of such events depends on the relative activation of the respiratory pump and upper airway dilator muscles (24). Obstructive apneas are more likely in weak patients who are also overweight (25). In patients with severe respiratory muscle weakness, some apneas that appear to be central may in fact be obstructive, incorrect classification being due to failure of external sensors to detect chest wall movements of reduced amplitude (26).

View larger version (17K): [in this window] [in a new window]   Figure 7. Section of sleep recording of SaO2 and transcutaneous PCO2 (TcCO2) in a patient with chronic myopathy, showing mild desaturation (SaO2 90%) in non-REM sleep and frequent periodic dips in SaO2 in REM sleep. The PCO2 shows progressive elevation during REM periods. Reprinted by permission from Reference 23.

View larger version (25K): [in this window] [in a new window]   Figure 8. Brief ( 2 minute) polysomnographic recording in REM sleep in a patient with chronic myopathy. The signals are as follows: SaO2, airflow (V·), posteroanterior motion of rib cage (RCPA) and abdomen (ABPA), electro-oculogram (EOG), and integrated surface electromyograms from inspiratory intercostals (EMGint) and diaphragm (EMGdi) (the ECG is superimposed on EMG signals). A–D, Periods of REM sleep. During periods A and C, marked irregular eye movements ("phasic" REM) are accompanied by reduced EMG activity and consequently reduced motion and flow with subsequent desaturation; rib cage and abdominal motion remain in phase, indicating central hypopneas. During periods B and D, eye movements are relatively quiescent and EMG activity increases with consequent increased motion and flow and subsequent recovery of SaO2 (increasing SaO2 during period C reflects the increased ventilation in period B). Reprinted by permission from Reference 24.

The timescale of progression from nocturnal to persistent diurnal hypercapnia in patients with chronic respiratory muscle weakness is not known.

Methodology
Polysomnographic techniques are described in detail elsewhere (28). To assess whether upper airway narrowing is a contributing cause of apneas or hypopneas may require use of a supraglottic or esophageal pressure sensor. Interpretation of recordings obtained by inductance plethysmography or other devices that measure rib cage and abdominal expansion is problematic in patients with quadriplegic or diaphragm paralysis. It is essential to check the polarity of the tracings and to compare phase relations awake and asleep.

Reliability of the devices for monitoring PCO₂ in sleep is currently doubtful and requires more study.

Advantages
Overnight oximetry is simple to perform.

Nocturnal measurements are more sensitive for detection of abnormal pulmonary gas exchange than daytime blood gases.

Disadvantages
Polysomnography is labor-intensive and relatively expensive. Current evidence suggests that nocturnal hypoxemia is a less good prognostic indicator than either vital capacity or awake Pa_CO2 (12, 29).

Applications
The role of sleep measurements in patients with respiratory muscle weakness is currently uncertain. Polysomnography may be useful in patients with daytime sleepiness and suspected nocturnal hypoventilation, perhaps especially if awake Pa_CO2 is borderline or only mildly elevated.

Marked REM-related desaturation is seen occasionally in patients with relatively normal daytime Sa_O2 (26). More typically, however, the severity of nocturnal desaturation is predictable from daytime measurements, with more marked desaturation in patients with lower daytime Pa_O2, higher Pa_CO2, and lower VC (23) (Figure 9) .

View larger version (20K): [in this window] [in a new window]   Figure 9. Relation of sleep hypoxemia to daytime blood gases and VC in 20 patients with chronic myopathy (regression line [solid line] ± 95% confidence limits [dashed lines]). The abscissa in each panel shows the nadir SaO2 in REM sleep. More severe REM desaturation occurs with lower awake PaO2 (top panel), higher awake PaCO2 (middle panel), and lower VC (lower panel). Reprinted by permission from Reference 23.

TESTS OF RESPIRATORY CONTROL
Rationale and Scientific Basis
The respiratory control system may be considered to have three functional components: (1) sensory receptors that provide information about the status of the respiratory system (only chemoreceptors that measure arterial PCO₂, PO₂, and pH are usually considered or tested, but there are many other sensory inputs of importance); (2) the central integrating circuits; and (3) the motor output to the respiratory muscles. The tests available are stimulus response tests, in which a receptor is stimulated and the motor output or a downstream mechanical effect of motor output, is measured. It is important to recognize that these tests are generally unable to separate the three functional components of the control system.

Minute ventilation and arterial PCO₂ are maintained at normal levels even with quite marked weakness of the respiratory muscles, implying that the control system compensates for the weakness by driving the respiratory muscles harder than normal. The mechanism by which the control system identifies muscle weakness and adjusts its motor output is unknown. The increased motor output is difficult to appreciate because it succeeds in generating only normal pressures, volumes, and flows. It is most readily apparent when accessory muscles or abdominal muscles are more active than normal during quiet breathing. If phasic contraction of scalenes, sternocleidomastoids, pectoral muscles, or abdominal muscles can be palpated, it is safe to conclude that respiratory motor output is above normal.

When respiratory muscles are chronically severely weak and arterial PCO₂ begins to rise, two explanations are possible. The muscles may be so weak that they cannot continually generate sufficient alveolar ventilation. Otherwise, an abnormality of the ventilatory control system may be allowing the PCO₂ to rise even though the muscles themselves are quite capable of keeping it normal. A gradual shift in the PCO₂ "set point" of the controller does seem to occur in some patients with muscle disease, as it does in some cases of sleep apnea and chronic obstructive pulmonary disease.

Laboratory tests of overall respiration that have been used to try to assess the control system include inhalation of hypercapnic or hypoxic gas mixtures to stimulate chemoreceptors, with measurements of ventilation or occlusion pressure to assess motor output, and sleep studies to monitor behavior of the control system during sleep.

In patients with weak muscles, interpretation of slopes of conventional ventilatory curves is clouded for several reasons.

• The output of the controller is abnormally high when ventilation is normal. The controller may therefore be on the nonlinear part of its normal response curve.

• The high motor neuron output cannot be measured directly and its mechanical effect (e.g., ventilation) is reduced in the presence of weakness.

• The response will become flat if ventilation nears the limit of respiratory muscle endurance and that limit may be only a short distance above resting ventilation.

Abnormal central control of respiration is well documented in bulbar poliomyelitis and other conditions affecting the central nervous system, presumably because of direct involvement of medullary respiratory centers. It has been suggested that certain muscle diseases are also associated with primary abnormalities of central respiratory control; these conditions include myotonic dystrophy, acid maltase deficiency, and other congenital myopathies. Impaired ventilatory responses to CO₂ and/or hypoxia have frequently been described, but in many cases, respiratory muscle function was assessed inadequately. In myotonic dystrophy it has been shown that the relations between hypercapnia and both maximum respiratory pressures and VC are similar to those in nonmyotonic diseases (30).

Occlusion pressure is the pressure generated in the airway (and by inference the pressure generated in the pleural space) by contraction of inspiratory muscles when the airway has been occluded at end expiration. It was introduced to separate hypoventilation due to high pulmonary resistance or elastance from hypoventilation due to a failure of the respiratory pump apparatus (i.e., the muscles, passive components of the chest wall, and the control system) (31, 32). Occlusion pressure amplitude does not directly assess either the degree of muscle weakness or the degree of neuronal adjustment to the weakness. P_0.1 is the pressure generated in the first 100 milliseconds of inspiration against an occluded airway. Its timing is such that it is not influenced by the conscious response to occlusion and as an index of ventilatory drive it has the advantage over ventilation of being independent of the mechanical properties of the lung (31). It is, however, dependent on the contractile state and function of the respiratory muscles and consequently on the lung volume at which it is measured. For example, because of the length–tension relationship of the muscles, a reduced value for a given neural output would be expected with pulmonary hyperinflation and an elevated FRC. On the other hand, if inspiration starts below equilibrium lung volume the value of P_0.1 recorded depends on relaxation of the expiratory muscles.

Values of P_0.1 are around 1 cm H₂O in normal subjects at rest, around 3 cm H₂O in patients with stable chronic obstructive pulmonary disease, and may be 10 cm H₂O or more in acute respiratory failure due to chronic obstructive pulmonary disease or acute respiratory distress syndrome. Such values reflect a high ventilatory drive consequent on a greatly increased mechanical load. Some, although not all, studies have suggested that in patients with chronic obstructive pulmonary disease receiving ventilatory support values greater than 4–6 cm H₂O are associated with failure to wean (33).

In patients with weak muscles, resting P_0.1 tends to be normal or slightly increased (34). In the model of acute respiratory muscle weakness provided by partial curarization of healthy subjects, the slope of P_0.1 response to CO₂ is increased even though the ventilatory response is reduced (35). However, in patients with chronic weakness the ventilatory and P_0.1 slopes are both diminished (even though resting P_0.1 is normal or increased). Hence, a reduced response in such individuals does not necessarily imply impaired ventilatory drive (30).

Methodology and Equipment
For assessment of ventilatory responses to hypercapnia or hypoxia (36), the subject inhales a gas mixture that causes a change in either arterial PO₂ or PCO₂. A plot of PO₂ (or PCO₂) against ventilation (or, for PO₂ response the algebraic constants describing a hyperbola) are compared with normal values. The induced change in blood gases may be continuous (rebreathing methods) or a few discrete points (steady state methods). Usually PCO₂ is held constant while PO₂ is changed and vice versa. Standard methods are available for measuring ventilatory responses during rebreathing (37, 38).

Steady state or quasi-steady state tests (39) are done simply by having the subject inhale a prepared mixture of gases, usually for 5 minutes (40). Judgments about the safety of inducing hypoxemia or acidosis are made clinically for individual patients. In chronically hypoxemic patients, transient responses to inhalation of pure oxygen may be useful and are safe (40).

For the measurement of P_0.1, it is essential to close the airway exactly at the point of zero flow. This is usually done by separating the inspiratory and expiratory lines with one-way valves and then closing the inspiratory line while the subject is exhaling. Conscious subjects must be unable to anticipate occlusions, which must be done silently and unexpectedly. Obstruction can be simply performed by inflating a balloon within the lumen of the inspired line or by closing a valve. A sensitive transducer and timer are used to record pressure at 0.1 second.

Advantages
A completely flat ventilatory response may identify defective chemoreceptor or brainstem function, but lesser abnormalities are difficult to interpret.

Occlusion pressure (P_0.1) is relatively easy to measure. Marked discrepancies between occlusion pressure and minute ventilation point to a lung disease causing substantial increase in airway resistance or lung elastance. Usually, however, such a problem is clinically evident and better evaluated by spirometry.

Disadvantages
Indices of ventilatory control have a wide normal range and are subject to overinterpretation.

Occlusion pressures in general, and P_0.1 in particular, are difficult to interpret without additional measurements of mechanics and control events through the whole respiratory cycle, which are usually not available. P_0.1 is a valid index of neural output only at FRC. Breath-to-breath scatter in the data requires averaging of many breaths to obtain precise results. The theoretical issues regarding measurement and interpretation have been reviewed (41).

Clinical Applications
These tests are seldom used in routine clinical assessment of stable patients. In acute respiratory failure, mouth occlusion pressure during unstimulated breathing may be of value in assessing respiratory drive and the likelihood of successful weaning.

Occlusion pressure has no proven clinical value in respiratory muscle disease but may occasionally be helpful by pointing to an unsuspected mechanical problem.

If a patient is known to have a mixed problem of muscle weakness and a lung disease (e.g., polymyositis plus interstitial pulmonary fibrosis) and the response of the controller to CO₂ or O₂ is being studied, P_0.1 can be measured in conjunction with ventilation as the response and may be a more reliable way of comparing the result with normal values.

CARBON MONOXIDE TRANSFER
Rationale and Scientific Basis
Single-breath CO diffusing capacity (transfer factor) (DL_CO) in patients with muscle weakness is usually normal or mildly reduced. Reduction is due to inability to achieve full distension of the lungs at TLC and consequent failure to expose all the alveolar surface to carbon monoxide. As with other extrapulmonary causes of lung volume restriction, the transfer coefficient (KCO) is often supernormal.

Advantages
The measurement is easily performed and well standardized.

Disadvantages
A reduced DL_CO is a nonspecific finding (but if accompanied by elevation of KCO it suggests extrapulmonary volume restriction). Any effects of respiratory muscle weakness on the measurements are indirect.

Clinical Applications
The pattern of normal or mildly reduced DL_CO and raised KCO directs attention to extrapulmonary conditions, that is, respiratory muscle weakness, pleural disease or rib cage abnormalities. Otherwise, the main role of measurement of CO uptake is in the recognition or exclusion of coexistent lung disease.

EXERCISE TESTING
In many patients with muscle weakness, exercise is limited, and therefore, maximum oxygen consumption is reduced because of weakness of the leg muscles rather than cardiorespiratory factors. The limited available data suggest that the relation of workload to oxygen consumption is normal, as also are indices of submaximal exercise performance (42).

Advantages
Formal testing allows confirmation and quantification of exercise incapacity and may aid elucidation of its mechanism.

Disadvantages
Exercise is limited by weakness of nonrespiratory muscles in many patients with neuromuscular disease. Exercise testing is poorly standardized in this patient population.

Clinical Applications
Exercise testing may help determine the main factor(s) limiting exercise capacity, especially if related or coexistent cardiac or pulmonary disease is present or suspected.

CONCLUSION
This Section of the Statement has explored the usefulness of analyzing the results of pulmonary function tests to infer alterations in respiratory muscle function. Some such inferences are as follows:

1. Respiratory muscle weakness reduces VC.
   
2. Expiratory muscle weakness can increase RV.
   
3. Reduction in chest wall and lung compliance, as a consequence of muscle weakness, reduces lung volumes, notably VC.
   
4. A fall in VC in the supine position, compared with when upright, suggests severe diaphragm weakness or paralysis.
   
5. With respiratory muscle weakness the maximal expiratory and inspiratory flow–volume loops show a reduction in effort-dependent flows (peak flows) and a sharp fall in end-expiratory flow.
   
6. Reduced maximal flows in neuromuscular disease may reflect poor respiratory muscle coordination.
   
7. Maximum inspiratory and expiratory flow–volume curves showing sawtooth oscillations are seen when the upper airway muscles are weak and also in patients with extrapyramidal disorders (e.g., Parkinson's disease).
   
8. Pa_O2 and Pa_CO2 are affected by muscle weakness. Mild weakness causes slight hypoxemia and hypocapnia; severe weakness causes hypercapnia, but only when strength is < 40% predicted. A raised bicarbonate level may suggest muscle weakness.
   
9. Respiratory muscle weakness may cause desaturation and hypercapnia during REM sleep.
   
10. CO transfer (DL_CO) in patients with muscle weakness is normal or mildly reduced but, as with other causes of extrapulmonary lung volume restriction, the transfer coefficient (KCO) is often raised.
    

	REFERENCES

TOP INTRODUCTION Introduction 1. Tests of Overall... REFERENCES 2. Tests of Respiratory... REFERENCES  3. Electrophysiologic Techniques... REFERENCES   4. Tests of Respiratory... REFERENCES    5. Assessment of Respiratory... REFERENCES     6. Assessment of Chest... REFERENCES     8. Tests of Upper... REFERENCES     9. Tests of Respiratory... REFERENCES     10. Assessment of Respiratory... REFERENCES

 

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	2. Tests of Respiratory Muscle Strength

TOP INTRODUCTION Introduction 1. Tests of Overall... REFERENCES 2. Tests of Respiratory... REFERENCES  3. Electrophysiologic Techniques... REFERENCES   4. Tests of Respiratory... REFERENCES    5. Assessment of Respiratory... REFERENCES     6. Assessment of Chest... REFERENCES     8. Tests of Upper... REFERENCES     9. Tests of Respiratory... REFERENCES     10. Assessment of Respiratory... REFERENCES

PRESSURE MEASUREMENTS
Muscles have two functions: to develop force and to shorten. In the respiratory system, force is usually estimated as pressure and shortening as lung volume change or displacement of chest wall structures. Thus, quantitative characterization of the respiratory muscles has usually relied on measurements of volumes, displacements, pressures, and the rates of change of these variables with time.

Several important considerations have to be kept in mind:

1. Pressures at a given point are usually measured as a difference from barometric pressure.
   
2. Pressures measured at a point are taken to be representative of the pressure in that space. Differences in pressure at different locations in normal subjects can arise from two causes: gravity and shear stress (1). Gravity causes vertical pressure gradients related to the density of the contents of the space. In the thorax this gradient is 0.2 cm H₂O · cm^-1 height and is related to lung density. In the abdomen, this gradient is nearly 1 cm H₂O · cm^-1 height. Pressure fluctuations are usually little affected by gravitational gradients. Deformation of shape-stable organs can cause local variations in pressure, such as those that occur when the diaphragm displaces the liver during a large forceful diaphragmatic contraction (2). Pleural pressure may not be uniform in patients with disordered lung architecture, particularly emphysema. The schematic drawing in Figure 1 shows relationships between pressures and intervening respiratory structures and equipment.
   
3. Pressure differences across structures are usually the relevant "pressures" for characterizing those structures. Table 1 lists pressures measured at a point and pressure differences across structures, which are usually taken in a direction such that positive pressure differences inflate the structure or lung.
   
4. A pressure difference between two points is always the pressure difference across two or more structures or groups of structures. For example, the pressure difference between the pleural space and the body surface in a breathing person is both the trans-chest wall (transthoracic) and the transpulmonary pressure.
   

View larger version (43K): [in this window] [in a new window]   Figure 1. Locations at which pressures can be measured, and pressure differences derived from them (see also Table 1). AbW = abdominal wall; aw = airway; Di = diaphragm; Eq = equipment; Lt = lung tissue; Pab = abdominal pressure; Palv = alveolar pressure; Pao = pressure at airway opening; Pbs = body surface pressure; Ppl = pleural pressure; rc = rib cage.

To test respiratory muscle properties, pressures can be measured either during voluntary maneuvers (see subsequent section) or during involuntary contractions, notably in response to phrenic nerve stimulation (see subsequent section). In the former, the synergistic action of several inspiratory or expiratory muscle groups is tested. In the latter, the pressure developed is specific to the contracting muscle(s).

The purpose of this article is to describe the methodology used to measure the various pressures for the assessment of respiratory muscle strength.

DEVICES FOR MEASURING PRESSURES
A comprehensive review of the techniques for measurement of pressures in respiratory physiology and of the associated problems was presented by Milic-Emili (6) in 1984.

Pressure Transducers
As for most pressure measurements of respiratory events, a frequency response flat up to 10–15 Hz is adequate to measure both dynamic and static pressures related to contractions of respiratory muscles. The frequency response of a transducer can be much altered by the characteristics of the systems attached to it, including balloons, tubing, and interconnecting fittings (7) (see subsequent section). Thus, testing the response characteristics of any transducer with the specific connectors and fittings that are to be used to make the measurements of pressure is highly recommended (7).

When differential pressure transducers are used, care must be taken that their two sides have identical frequency responses. Calibration is best made with water manometers. Electrical calibration is acceptable, but should be checked regularly with a water manometer.

The required range and sensitivity of the transducers depends on the test in question. Phrenic nerve stimulation in disease may develop pressures as low as a few centimeters of water, whereas maximal static maneuvers in healthy subjects can be associated with positive and negative pressures exceeding 200 cm H₂O. It may be possible to use a single type of transducer for all respiratory muscles tests, provided that it is sufficiently sensitive, with a resolution of approximately 0.5 cm H₂O and a range ± 200 cm H₂O. Pressure differences between two points can be measured directly with two catheters connected to a single differential pressure transducer.

Excellent pressure transducers, with such characteristics, are commercially available, including devices based on a metal "membrane." More recently, other types of transducer that provide good results (e.g., piezoelectric transducers) have been made available at lower cost.

Probes for "Internal" Pressures
Balloon catheter systems.
The balloon catheter system is the most widely used method for recording esophageal pressure (Pes, Poes; see APPENDIX for a list of abbreviations) as a reflection of pleural pressure (Ppl), and gastric pressure (Pga) as a reflection of abdominal pressure (Pab) (8). Air-containing latex balloons are sealed over catheters, which in turn transmit pressures to the transducers. Single- and double-balloon catheter systems are commercially available, but can be made in-house at low cost. Double-balloon catheters associated with an electromyograph (EMG) electrode have been used (9–11). When choosing or preparing a balloon catheter system, careful attention must be given to its physical characteristics. Indeed, the volume of the balloon, its volume–pressure characteristics, and the dimensions of the catheter can influence the measurement of pressure and introduce major errors. Standardization has been proposed (12).

For the measurement of Pes, good results have been provided by latex balloons 5–10 cm long, 3.5–5 cm in perimeter, and with a thin wall (8, 13, 14). For accurate transmission of pressure, air should be introduced into the balloon until it is fully distended to smooth out folds, and then most of the air removed so that a volume is retained at which the rubber is unstretched without distending the esophagus significantly. A volume of 0.5 ml is adequate for balloons with these characteristics. The volume displacement coefficient of the balloon catheter–transducer system should be measured, particularly if the balloon will measure positive pressures, to ensure that the pressure level to be measured does not completely empty the balloon into the catheter and transducer. Thus, if high positive pressures are to be measured (e.g., for Pes during maximal expiratory maneuvers) a volume of 0.5 ml may be inadequate (6). Balloon volumes should be checked repeatedly during measurements.

For the measurement of Pga, balloon volume is less crucial and measurements can be made with a balloon volume of 1–2 ml, given that this remains within the range of volume over which the rubber is unstretched. If studies of relatively long duration are planned, the walls of the gastric balloon should be thicker than those of esophageal balloons to increase resilience to gastric secretions.

Respiratory muscle studies can involve dynamic maneuvers with high rates of change in pressure (e.g., sniffs and twitches) resulting in a significant risk of a damped signal if the frequency response of the measuring system is inadequate, as may occur if the internal diameter of the catheter is too small or the gas volume too large. Polyethylene catheters with an internal diameter 1.4–1.7 mm and 70–100 cm in length provide, when associated with adequate transducers, an appropriate frequency response (6).

The catheter should be reasonably stiff, with a series of holes arranged in a spiral pattern over the entire portion of the catheter covered by the balloon, because the gas in the balloon tends to shift to the point where the pressure surrounding it is most negative, i.e., the top of the balloon in upright subjects.

Liquid-filled catheters.
Fluid-filled catheter systems have been employed, mainly in neonates and small animals for study of respiratory mechanics. Their advantage is that the transmission of pressure involving a noncompressible fluid (usually water) gives a high-frequency response. The catheters can, thus, be thinner than for balloons, theoretically reducing discomfort. An important practical difficulty is the need for regular flushing of the catheter, to avoid plugging of distal holes and to keep the catheter–manometer system free of air bubbles, which may dampen the measured pressure. Another drawback is that while the gas bubble in the balloon migrates to the point where the pressure is least (which is thought to minimize artifacts in the esophagus and to locate pressure at the surface of the gastric air bubble in the stomach) in a liquid-filled catheter, pressure is always measured at the end of the catheter, which may not be the optimal site. Respiratory muscle studies in adult humans with this technique are limited or not described, and its place in this context is probably limited.

Catheter-mounted microtransducers.
Catheter-mounted microtransducers, often referred to as Millar catheters (15, 16), have a level of performance comparable to that of balloon catheters (17, 18). Their management during long studies is probably easier, with a lower risk of technical problems (e.g., leaking balloons), and they may be easier to tolerate for the subject. Their frequency response is high, which may eliminate the phase lag sometimes seen with balloon catheters during extremely rapid pressure changes. However, catheter-mounted microtransducers record pressure at a single focused point so that the measured Pes may not be as representative of Ppl as balloon catheters, which sample pressure at the point where it is most negative. They are also much more expensive than balloon catheter systems, and may be difficult to sterilize and reuse with confidence.

Other systems.
Other systems exist to measure pressures in humans, including fiberoptic sensors. Fiberoptic sensors have long been used for measurement of intracerebral pressures in neurosurgery (19) (for review, see Yellowlees [20] and Shapiro and coworkers [21]). They are probably adequate to measure respiratory pressures (22), and may offer advantages over other devices, including decreased chance of false measurements due to occlusion with water or mucus, less chance of kinking, and, possibly, more rapid response to pressure changes. This remains to be precisely established, and, apparently, no study of fiberoptic systems in respiratory muscle tests is available.

Devices for Measurement of Airway Opening Pressure
Air-filled catheter systems are commonly used to measure pressures in airways and at the mouth. Airway opening pressure (Pao) is usually sampled from a side tap (lateral pressure) in a mouthpiece (Pmo), tracheal tube (Ptr), face mask (Pmask), or from a nostril plug (Pnas) (23). For nasal pressure to reflect airway pressure there must be free communication between the nostrils and mouth, with nasal flows. If Pao is measured from a side tap of a mouthpiece or a tracheal tube during a maneuver that involves gas flow, the cross-section of the device through which the subject breathes must be large enough to avoid measurement errors due to the Bernoulli effect (24). In some cases, Pao serves to estimate alveolar pressure (PA, Palv) during dynamic respiratory efforts made against an obstructed airway (e.g., mouth pressure response to phrenic nerve stimulation). For Pao to reflect PA accurately the transmission of pressure from the alveoli to the airway has to be very fast. The time constant of transmission is the product of the flow resistance offered by the airways (Raw) and the compliance of the extrathoracic airways (Cuaw) including the mouth, cheeks, and equipment. In practice the internal volume of the measuring equipment (mouthpiece, face mask, tracheal tube) contributes negligibly to the time constant (6), but should be minimized in patients with an already increased time constant, such as patients with chronic obstructive pulmonary disease (COPD). The compliance of the cheeks can be minimized by holding them rigid with the hands.

TECHNIQUES FOR PRESSURE MEASUREMENT
Esophageal, Gastric, and Transdiaphragmatic Pressures
Scientific basis.
Transdiaphragmatic pressure (Pdi) is defined as the difference between Ppl and Pab (13) and, in practice, is generally equated to the difference between Pes and Pga, so that Pdi = Pga - Pes (where Pes is usually, but not always, negative). This is contrary to most pressures across a structure, which are taken at a direction such that positive pressures inflate (e.g., positive transpulmonary pressures inflate the lung). For this reason Pdi is also sometimes defined as Pdi = Pes - Pga. As the diaphragm is the only muscle in which contraction simultaneously lowers Pes and increases Pga, an increase in Pdi is, in principle, the result of diaphragmatic contraction unless there is passive stretching. An inspiratory effort produced with a completely passive unstretched diaphragm is associated with a negative change in Pes and Pga but no change in Pdi. This assumes that changes in Pes or Pga induced by mechanisms other than diaphragm contraction are uniformly transmitted across the diaphragm from one compartment to the other. This is probably true when the diaphragm is relaxed (6, 13) at functional residual capacity (FRC), but may be modified when the diaphragm is stretched, as at low lung volumes.

Methodology.
Pes and Pga are most often measured by passing a pair of probes, generally balloon catheters (see previous passages), through the nose, following local anesthesia of the nasal mucosa and pharynx. Their position is usually assessed by asking the subject to perform sharp sniff maneuvers while monitoring the signal on an oscilloscope or computer screen. A simple technique is to advance both probes well into the stomach, as judged by a positive deflection during a sniff and then to withdraw one of them until the sniff-related pressure deflection first becomes negative, indicating that the balloon has entered the esophagus. It is then withdrawn a further 10 cm. The validity of the Pes measurement can be checked by matching Pes to Pao during static Mueller (inspiratory) maneuvers (the dynamic occlusion test) (6, 12, 14). Displacement of balloons is minimized by taping the catheters to the nose. The distance between the nostril and the tip of the balloons varies with the size of the subject, but is usually 35–40 cm for Pes and 50–60 cm for Pga in adults.

Placing the probes becomes more difficult when the subject cannot perform voluntary inspiration (e.g., with anesthetized patients, diaphragmatic paralysis, cognitive impairment, or muscle incoordination). The pressure signals during a swallow can then be useful: A balloon is positioned in the esophagus if swallowing is associated with a slow, powerful rise in pressure, whereas if this does not occur the balloon is likely to be in the stomach. Measurement of balloon distance from the nostril can be a useful indication of its position.

It is advisable to measure Pes and Pga separately by using two pressure transducers, with Pdi derived from a third differential pressure transducer or reconstructed electronically offline. This allows the investigator to monitor balloon position and detect confounding events such as esophageal spasms, as well as recording the three pressures independently. Resting Pga is usually positive with respect to atmosphere due to hydrostatic pressure in the abdomen. For respiratory muscle measurements Pga is conventionally taken as zero at resting end expiration.

Advantages.
Pdi is specific for diaphragm contraction (see previous passages). Separate measurements of Pes and Pga provide information on the components of this contraction and Pes on the inspiratory driving pressure (Pes/Pdi ratio).

Disadvantages.
The procedures require the subject's co-operation and occasionally untrained healthy volunteers can fail to increase Pdi because of lack of coordination, in the absence of any diaphragmatic abnormality (25). This is, however, unusual during the inspiratory phase of quiet breathing at rest. The measurements are mildly uncomfortable, both initially (when swallowing the catheters) and during studies. However, the discomfort of swallowing a thin catheter is small compared with other established medical procedures and scarcely "invasive." Good-quality equipment and adequate practice minimize the discomfort, but some skill is necessary and passing the probes can be time-consuming. Particular care must be taken in patients with impaired swallowing, as well as esophageal diseases, or disorders at the level of the gastroesophageal sphincter.

Mouth Pressure and Nostril Pressure
Scientific basis.
Pmo is easy to measure and changes may give a reasonable approximation of change in alveolar pressure and thus Pes, providing there is relatively little pressure loss down the airways, or across the lungs. This may be realistic with normal lungs, particularly when changes in lung volume are small, but is unlikely to be fulfilled in patients with severe lung or airway disease. When used in combination with voluntary static and dynamic maneuvers at FRC, Pmo provides a global index of the action of synergistic respiratory muscles. When the diaphragm contracts in isolation against a closed airway, as with phrenic nerve stimulation, Pmo may be a useful reflection of Pdi.

Pnas is also easy to measure (see VOLITIONAL TESTS OF RESPIRATORY MUSCLE STRENGTH) but has the same caveats as Pmo.

Methodology.
Pmo is measured at the side port of a mouthpiece. It should be possible to occlude the mouthpiece at the distal end and a small leak should be incorporated to prevent glottic closure during inspiratory or expiratory maneuvers (26). The type of mouthpiece used can significantly influence the results (27). The issue of the lung volume at which Pmo should be measured during static efforts is addressed in the section on volitional tests (see subsequent section), and the various maneuvers that can be used to obtain useful Pmo data during phrenic nerve stimulation are described in the section on phrenic nerve stimulation (see subsequent section).

Pnas is measured with a polyethylene catheter held in one nostril by a soft, hand-fashioned occluding plug; respiratory maneuvers are performed through the contralateral nostril (23).

A standard mouthpiece for Pmo, or a nasal plug (custom made or commercially available) for Pnas, and one pressure transducer are required. Portable Pmo devices (28) are useful for screening and bedside studies.

Advantages of mouth pressure and nasal sniff pressure.
The main advantage of Pmo and Pnas are their simplicity and ease of use, both for the operator and for the subject.

Disadvantages of mouth pressure and nasal sniff pressure.
The measurement of Pmo does not allow the investigator to discriminate between weakness of the different respiratory muscles. When Pmo or Pnas is used as a substitute for Pes during dynamic maneuvers (sniff test, phrenic nerve stimulation), glottic closure or airway characteristics may prevent adequate equilibration.

VOLITIONAL TESTS OF RESPIRATORY MUSCLE STRENGTH
The principal advantage of volitional tests is that they give an estimate of inspiratory or expiratory muscle strength, are simple to perform, and are well tolerated by patients. Passage of balloon catheter systems into the esophagus and/or stomach is not usually required. However, it can be difficult to ensure that the subject is making a truly maximal effort. Although normal subjects can potentially activate peripheral and respiratory muscles fully during voluntary efforts (29), even experienced physiologists cannot always do this reliably for respiratory efforts (30) and naive subjects have even greater difficulty (31). Thus, it is hard to be certain whether low mouth pressure measurements truly represent reduced strength, or merely reduced neural activation. Indeed, there may be some activation of agonist muscles simultaneously (32). However, in practice a normal result can be of value in precluding clinical weakness.

Maximal Static Inspiratory and Expiratory Pressure
Scientific basis.
Measurement of the maximum static inspiratory pressure that a subject can generate at the mouth (PImax) or the maximum static expiratory pressure (PEmax) is a simple way to gauge inspiratory and expiratory muscle strength. The pressure measured during these maneuvers reflects the pressure developed by the respiratory muscles (Pmus), plus the passive elastic recoil pressure of the respiratory system including the lung and chest wall (Prs) (Figure 2 [33]). At FRC, Prs is zero so that Pmo represents Pmus. However, at residual volume (RV), where PImax is usually measured, Prs may be as much as -30 cm H₂O, and thus makes a significant contribution to PImax of up to 30% (or more if Pmus is decreased). Similarly, PEmax is measured at total lung capacity (TLC), where Prs can be up to +40 cm H₂O. Clinical measures and normal values of PImax and PEmax do not conventionally subtract the respiratory system recoil.

View larger version (19K): [in this window] [in a new window]   Figure 2. Relationship of muscle and respiratory pressures at different lung volumes. Vertical axis: lung volume as a percentage of vital capacity (%VC). Horizontal axis: alveolar pressure in cm H2O. The broken lines indicate the pressure contributed by the muscles. Pmus = pressure developed by the respiratory muscles; Prs = pressure of the respiratory system. Reprinted by permission from Reference 33.

Because of the force–length relationship and the varying contribution of Prs, PImax and PEmax vary markedly with lung volume (38). Subjects find it easier to maximize their inspiratory efforts at low lung volumes and expiratory efforts at high volumes; therefore, by convention and to standardize measurement, PImax is measured at or close to RV and PEmax at or close to TLC. In some laboratories PImax and PEmax are measured at FRC, and this may be more accurate for certain research studies, but in this case the lung volume should be specifically stated (39). In patients with abnormally high lung volumes (e.g., patients with COPD), a low PImax may partly reflect the shortened inspiratory muscle fiber length associated with increased lung volume at RV rather than reduced inspiratory muscle strength (Figure 3) . Furthermore, hyperinflation is often associated with intrinsic positive end-expiratory pressure (PEEPi), so inspiratory efforts start from a negative airway pressure. Thus, if PImax is measured as the maximal negative airway pressure, it will underestimate the actual pressure generated by the inspiratory muscles. Optimally, under such circumstances, PImax should be measured as the total negative deflection of the occluded airway pressure during the inspiratory effort, including the effort required to draw down PEEPi.

View larger version (14K): [in this window] [in a new window]   Figure 3. Relationship between maximal static respiratory pressure (PImax, PEmax) and lung volume. Pressures are expressed as a percentage of maximum and the lung volume is expressed as a percentage of TLC. Symbols are data from different studies (39). Example A represents a patient with emphysema whose RV is 85% TLC, at which lung volume his predicted PImax is only 50% of that at normal RV. Conversly, Example B represents a patient with lung fibrosis with TLC of 55% predicted, at which volume her PEmax is 82% maximum. Reprinted by permission from Reference 39.

View larger version (22K): [in this window] [in a new window]   Figure 4. Measurement of maximal static respiratory pressures. A flanged mouthpiece with a nose clip is the preferred technique. A small leak is introduced into the system, and a valve system allows a normal breath to be followed by a maximum maneuver.

View larger version (23K): [in this window] [in a new window]   Figure 5. (A) A typical pressure tracing from a subject performing a maximum expiratory maneuver (PEmax). A peak pressure is seen and the 1-second average is determined by calculating the shaded area. (B) A pressure tracing from a subject performing a maximum inspiratory maneuver (PImax).

Advantages.
The pressures measured at the mouth during maximum inspiratory or expiratory maneuvers are widely used specific tests of respiratory muscle strength. Normal values are available for adults, children, and the elderly. The tests are not complicated to perform and are well tolerated by patients. The recent development of hand-held pressure meters means the technique may be easily used at the bedside (28).

Disadvantages.
These tests are volitional and require full cooperation. Accordingly, a low result may be due to lack of motivation and does not necessarily indicate reduced inspiratory or expiratory muscle strength.

Normal values and applications.
The recorded values of PImax and PEmax may be compared with published normal values (Table 2). The values that most closely reflect the protocol described here with a flanged mouthpiece, are those obtained by Wilson and coworkers (43). Normal values for the elderly (46–48) and children (43, 49–51) have been reported. The normal ranges are wide (Table 2), so that values in the lower quarter of the normal range are compatible both with normal strength and with mild or moderate weakness. However, a PImax of -80 cm H₂O usually excludes clinically important inspiratory muscle weakness. Values less negative than this are difficult to interpret and in such circumstances it would be appropriate to undertake more detailed studies. A normal PEmax with a low PImax suggests isolated diaphragmatic weakness.

Regional measurements.
Static respiratory muscle pressures generated against a closed airway can be recorded from balloon catheter systems passed into the esophagus (see TECHNIQUES FOR PRESSURE MEASUREMENTS) to measure Pes as a reflection of Ppl or into the stomach where Pga can be used to reflect Pab. Esophageal pressure does not include lung elastic recoil pressure but does include chest wall recoil pressure. The main indication for balloon catheter measurements of maximum respiratory muscle pressures is to estimate the strength of the separate muscle groups, notably the diaphragm (from Pdi), or to measure strength when the patient is unable to maintain a proper seal around the mouthpiece.

With the balloon catheters in place, various maneuvers can be used to assess global inspiratory muscle or diaphragm strength. These tests are usually performed at FRC. In the Mueller (maximal inspiratory) maneuver the diaphragm and inspiratory muscles are contracted with the aim of creating the biggest negative thoracic pressure without regard to abdominal pressure. However, this usually does not generate maximum Pdi (25, 52). As an alternative, the subject may perform an expulsive maneuver, wherein the individual is requested to "bear down as for defecation" and simultaneously superimposes a Mueller maneuver. When given visual feedback, this complex maneuver can be mastered by trained subjects to give the largest values of Pdi (up to 240 cm H₂O or more) (53). It may reflect nearly maximal neural activation of the diaphragm, perhaps with fiber lengthening (52, 54). However, the technique is difficult for naive subjects and in the clinical setting (55). Twitch occlusion studies have confirmed that such maneuvers can produce maximal neural activation of the diaphragm (56).

Advantages and disadvantages for regional measurements.
The measurement of maximum static transdiaphragmatic pressure, PI,di,max, produced during the described maneuvers, can provide specific information about maximal diaphragm strength. However, these tests require passage of balloon catheters and the necessary coordination is difficult for naive subjects and patients. There are limited normal data. It is difficult to control for muscle (fiber) length, and for velocity of shortening. This test is recommended only as a research tool or in respiratory muscle function laboratories with specialized expertise.

Sniff Tests
Scientific basis.
A sniff is a short, sharp voluntary inspiratory maneuver performed through one or both unoccluded nostrils. It involves contraction of the diaphragm and other inspiratory muscles. To be useful as a test of respiratory muscle strength, sniffs need to be maximal, which is relatively easy for most willing subjects, but may require some practice.

The sniff was described in 1927 as a radiological test of diaphragm paralysis because, in normal subjects, it was associated with crisp diaphragm descent during inspiration (57, 58). Esau and coworkers (59) suggested that a short, sharp sniff would approximate the diaphragm contraction elicited by a brief stimulation of the phrenic nerves (59, 60). Miller and coworkers (61) showed that normal subjects generated greater Pdi during maximal sniffs than during maximal static inspiratory efforts, perhaps because the maneuver achieves rapid, fully coordinated recruitment of the inspiratory muscles (62). The detailed respiratory mechanics of this dynamic maneuver have been little studied, but numerous studies using the sniff in normal subjects and patients have found it to be a robust measure. The nose appears to act as a Starling resistor, so that nasal flow is low and largely independent of driving pressure, Pes (63). Pdi measured during a sniff (Pdi,sn,max) reflects diaphragm strength and Pes reflects the integrated pressure of the inspiratory muscles on the lungs (Figure 6) .

View larger version (11K): [in this window] [in a new window]   Figure 6. Esophageal (Poes), gastric (Pg), and transdiaphragmatic (Pdi) pressures measured during maximum voluntary sniffs in a normal subject and in a patient with severe diaphragm weakness. The normal subject reproducibly generates a Pdi of 120 cm H2O (11.8 kPa), whereas the weak patient can generate only 15 cm H2O (1.5 kPa).

Methodology.
For measurement of maximal sniff pressures, patients are encouraged to make maximum efforts. Sniffs can be achieved only when one or both nostrils are unoccluded, to allow the passage of air. An occluded sniff may be called a "gasp," and is more difficult for subjects to perform reproducibly. Subjects should be instructed to sit or stand comfortably, and to make sniffs using maximal effort starting from relaxed end expiration. Detailed instruction on how to perform the maneuver is not necessary, and may be counterproductive. However, subjects should be exhorted to make maximal efforts, with a rest between sniffs. Most subjects achieve a plateau of pressure values within 5–10 attempts.

Transdiaphragmatic pressure during sniff.
Esophageal and gastric balloons are passed by the usual technique. Transdiaphragmatic pressure during sniff (Pdi,sn) is reasonably reproducible within normal subjects, although there is wide variability between subjects (61) (Table 3). The values tend to be as large, or larger, than Pdi during maximum static inspiratory efforts (61).

Nasal sniff pressure.
Pressure is measured by wedging a catheter in one nostril. Various techniques for wedging are available including foam, rubber bungs, and dental impression molding. The subject sniffs through the contralateral unobstructed nostril. The pressure in the obstructed nostril reflects the pressure in the nasopharynx, which is a reasonable indication of alveolar pressure. This in turn approximates esophageal pressure, particularly if the lungs are normal with a mean Pnas/Pes ratio of 0.92 (64, 66). In COPD, nasal sniff pressure (Pnas,sn) tends to underestimate esophageal pressure during sniff (Pes,sn) but can complement PImax in excluding weakness clinically (67).

Mouth and nasopharyngeal pressures can also be measured, and also reflect alveolar pressure, but are less easy for the subject than nasal pressure and have no significant advantages (65) (Figure 7) .

View larger version (16K): [in this window] [in a new window]   Figure 7. Simultaneous pressure measurements from esophageal (Pes), nasopharyngeal (Pnp), and mouth (Pmo) balloons in a normal subject performing sniffs of increasing strength, to illustrate close correlation of the waveforms. Reprinted by permission from Reference 65.

Advantages.
The sniff is easily performed by most subjects and patients and requires little practice. It is relatively reproducible and has a smaller range of normal values than mouth pressures (61, 62). It is a useful voluntary test for evaluating diaphragm strength in the clinical setting (55), giving equal or greater pressures than maximal static efforts (61, 68).

It is possible to achieve greater transdiaphragmatic pressures by certain maneuvers, such as the modified Mueller maneuver (see previous passages), in highly trained and well-motivated subjects. This may be important in physiological studies but is not usually clinically relevant.

Sniff nasal pressure is technically simple.

Disadvantages.
The pressures measured during a sniff may be less than maximal static values because of shortening of the inspiratory muscles (pressure–velocity relationship) (69). The average volume change during a sniff is approximately 500 ml with some gas rarefaction, which may be somewhat more than the volume by which gas expands during a static maneuver against a closed airway (63).

Sniffs are difficult or impossible if there is upper airway distortion, and particularly if the nose is completely obstructed. It may be difficult to pass the balloons if there is severe bulbar weakness, but this would not preclude measurement of Pnas.

Sniffs are voluntary maneuvers and, therefore, poorly motivated subjects may perform submaximal efforts. These can often, but not always, be detected as variability tends to be greater than for maximal maneuvers.

The sniff generates rapid pressure changes, so measurement requires a catheter system and transducer with a higher frequency response (see previous passages) than for static maneuvers.

Applications.
Maximal sniffs have been widely used and validated as reproducible and reliable tests of diaphragm or global inspiratory muscle function. This test can, therefore, be used in research studies, although care must be taken with reproducibility, as in any voluntary maneuver.

The sniff maneuver is a useful part of the clinical evaluation of respiratory muscle strength and correlates well with response to therapy (Figure 6) (68). The normal values are shown in Table 3 (61). There is a wide normal range, reflecting the wide range of normal muscle strength in different individuals. In clinical practice Pdi,sn,max values greater than 100 cm H₂O in males and 80 cm H₂O in females are unlikely to be associated with clinically significant diaphragm weakness (55). Values of maximal sniff Pes or Pnas numerically greater than -70 cm H₂O (males) or -60 cm H₂O (females) are also unlikely to be associated with significant inspiratory muscle weakness. However, these reflect the integrated pressure of all the inspiratory muscles and it is possible that there could be a degree of weakness of one or more of these muscles that would not be detected at this level.

Cough Tests
Scientific basis.
Measurement of pressure during cough is of interest because the main expiratory muscles, the abdominal muscles, are also those used in cough. Reduced cough pressure is of clinical importance because it may predispose to chest infections. Also, in some patients technical difficulties preclude measurement of mouth pressure during a static maximal expiratory maneuver (PEmax); in these patients measurement of maximal cough pressures is an alternative measurement technique.

A normal cough consists of four phases: inspiratory, compressive, expulsive, and relaxation (70). For cough to be a measurement of expiratory muscle strength, two aspects require consideration: how standard is the maneuver and what should be measured.

Expiratory muscle strength is influenced by lung volume (71). It is normal to take a deep breath before a maximal cough. Thus, although no instructions are given concerning the magnitude of inspiration, the actual lung volume is probably relatively constant for a given individual during serial measurements. Compression requires a functional glottis; in some disorders, for example bulbar type amyotrophic lateral sclerosis, this may not be present (72). A glottis that does not open immediately causes an uncomfortable choking sensation and makes measurement of mouth pressure (during either a PEmax maneuver or a cough) difficult, but would not exclude obtaining useful measurements from a gastric or esophageal balloon (73).

Theoretically, the peak cough pressure could be measured at the mouth, esophagus, or stomach, but measurements at the mouth have not been reported. Pdi is generated during cough (74) and forced expiration (75) so that Pes,co is always less than Pga,co (76). This Pdi can be substantial in a few subjects (76); it may be due to active contraction of the diaphragm, or passive stretching. In general, gastric pressure can be viewed as a reasonable measure of abdominal muscle strength. The surface EMG from abdominal muscle also varies with cough intensity (77), but difficulties in standardizing it between measurements make this relatively impractical as a measurement of strength.

Methodology.
After passage and positioning of appropriate balloon catheters the subject is asked to cough as forcefully as possible. Visual feedback seems to be helpful, as with the diaphragm (53). Peak pressures are measured between the baseline at relaxed end-expiratory lung volume, and peak pressure (Figure 8) .

View larger version (16K): [in this window] [in a new window]   Figure 8. Pressures during a maximal voluntary cough in a normal subject showing high positive gastric pressures generated in abdomen (Pga; thick line) and esophagus (Pes) with low Pdi during the maneuver.

It would, theoretically, be possible to measure the pressure generation during an induced (e.g., with citric acid) cough in patients unable to cough voluntarily, for example, those in intensive care units.

Cough pressures can be large, so it is necessary to have an adequate volume of air in the balloon, to avoid compression of the gas bubble in the balloon and its displacement into the catheter–transducer system.

Normal ranges.
No normal data exist from large studies. Black and Hyatt (78) found PEmax and cough esophageal pressures comparable in a subgroup of their subjects. Other authors have found lower values in patients with COPD (79). The mean maximal Pga,co in a small group of normal subjects 20–75 years of age was 230 cm H₂O for men and 166 cm H₂O for women, with lower limits of 160 cm H₂O for men and 120 cm H₂O for women (76).

PRESSURES OBTAINED VIA PHRENIC NERVE STIMULATION
Scientific Basis
The diaphragm is innervated exclusively by the phrenic nerve and thus phrenic nerve stimulation (PNS) provides a specific means to investigate the diaphragm independent of other inspiratory muscles. Indices that may not be specific for diaphragm contraction when measured during voluntary maneuvers do relate to the diaphragm when they are derived from PNS. Examples include surface recordings of the electromyogram of the costal diaphragm (EMGdi), Pmo or Pes, and phonomyogram (PMGdi). The other major feature of PNS is that it eliminates the influence of the central nervous system. PNS can give important information about the mechanical function of the diaphragm, namely, about how the force of contraction is transformed into pressure, and can be used to confirm whether a contraction is maximal. PNS superimposed on naturally occurring or voluntary contractions (twitch occlusion principle; see subsequent section) can provide an objective estimate of the maximal voluntary pressure that the diaphragm can produce.

Methodology
Since 1980, PNS has been investigated as a technique for elucidating mechanical aspects of diaphragm function. The 1989 National Heart, Lung, and Blood Institute (NHLBI) workshop on respiratory muscle fatigue identified it as one of the most promising techniques in this field (80).

The stimulus to the nerve, which can be an externally applied electric field or secondary currents surrounding a magnetic field (see MAGNETIC STIMULATION), elicits synchronized activation of motor units and subsequent muscle contraction. The effects of phrenic nerve stimulation can be studied both electrophysiologically (see STIMULATION TESTS in Section 3 of this Statement) and mechanically (this Section).

Four main PNS techniques have been used, mostly in healthy volunteers, less often in patients. Two of them, needle stimulation (81, 82) and implanted wire stimulation (83), are invasive, with the risk of hematoma and phrenic nerve damage. Needle stimulation is not now recommended, and is not further discussed. Implanted wire stimulation is probably safer, and may be a convenient means to obtain repeated twitches over long periods of time. The two others techniques, transcutaneous electrical PNS (ES) and magnetic stimulation (MS), have been more extensively studied and have minimal side effects.

Subjects in Phrenic Nerve Stimulation
For laboratory and clinical studies subjects should be sitting in a comfortable chair. Headrests may be helpful for ES.

Lung volume.
A major condition for evaluating the pressure response to PNS is adequate relaxation of the respiratory muscles at FRC, or within approximately 500 ml (84).

Posture.
Most studies have been performed with seated subjects, but twitch transdiaphragmatic pressure (Pdi,tw) seems to be little altered by posture in contrast to sniff transdiaphragmatic pressure (Pdi,sn) and static Pdi (56, 65, 84, 85). This feature could be useful in an intensive care unit (ICU) setting.

Abdominal binding.
Abdominal binding has little effect on voluntary Pdi values (86), but markedly increases Pdi,tw (56, 65, 84, 87). The rationale for binding the abdomen during PNS is to make the contraction closer to isometric than with a compliant abdominal wall; this may be appropriate for physiological studies (56, 88, 89). In a clinical setting it is difficult to standardize a binding technique and so the abdomen is usually unbound.

Transcutaneous Electrical Phrenic Nerve Stimulation
Scientific basis.
An externally applied electrical field induces depolarization of phrenic nerve fibers, at mid-distance between the electrode and the cathode. If the stimulus is intense enough, all fibers are activated synchronously, giving predictable and reproducible results (see STIMULATION TECHNIQUES in Section 3 of this Statement).

Methodology.
For bilateral ES, the operator should stand behind the seated subject. The skin in the stimulated region is degreased and mildly abraded to decrease its electrical impedance, allowing lower current intensities. Monopolar or bipolar electrodes can be chosen (Figure 9) . For monopolar electrodes, the anode is usually taped on the skin below the clavicle medially, and the cathode is held in the hand. Monopolar electrodes probably make it easier to find the nerve because a greater number of spots can be tested. However, because the electrical field is less focused than with bipolar electrodes, it may be more difficult to avoid costimulation of the adjacent sternocleidomastoid muscle or the brachial plexus. Bipolar electrodes are more specific but are also slightly more difficult to use. Various models of bipolar electrode are commercially available. They generally include felt tips 5 mm in diameter with an interelectrode distance of approximately 2 cm. When performing stimulation, the tips of the electrode should be soaked in saline and the cathode should be proximal.

View larger version (13K): [in this window] [in a new window]   Figure 9. Technique for transcutaneous electric stimulation of the phrenic nerve. (A) Use of a bipolar electrode to locate and stimulate the phrenic nerve; (B) the monopolar technique. The phrenic nerve is usually found underneath the posterior border of the sternocleidomastoid muscle, at the level of the cricoid cartilage. The operator stands or sits beside (possible for unilateral stimulation) or behind (for bilateral stimulation) the patient and uses the electrode to push the muscle forward. Firm pressure on the soft tissues of the neck avoids changes in the relationship between the electrode and the nerve.

Equipment.
A constant-current stimulator capable of delivering square wave shocks of 0.1-millisecond duration and of modulable intensity is used, which should include two synchronized outputs to allow bilateral stimulation. Two triggered EMG amplifiers and a display should be available, so that the muscle action potential (M wave) can be checked online by the operator. Several manufacturers provide complete machines that offer a wide panel of sophisticated stimulation and EMG acquisition options. Stimulators and amplifiers can also be bought separately.

Advantages.
If skillfully performed, ES generates a "pure" diaphragmatic contraction. The corresponding output is thus representative of diaphragm properties alone. ES can be reproducible in skilled hands.

Disadvantages.
The stimulus intensities required to achieve supramaximal stimulation can be uncomfortable. From the technical point of view, there are several difficulties. First, maintaining optimal contact between the stimulating electrode and the nerve can be difficult. It may be necessary to impose a significant degree of pressure on the soft tissues of the neck, which can be painful for the subject and awkward for the operator, particularly in obese or old subjects, or those with hypertrophy of neck muscles. Skin-taped stimulating electrodes have been used in healthy volunteers (90), but they probably do not guarantee reproducible results in all settings. Neck- and electrode-stabilizing devices have been proposed (10, 85) that can be effective, but are cumbersome. Second, it is sometimes impossible to dissociate PNS from brachial plexus stimulation, particularly at high current intensities. This can be a source of discomfort for the subject, and can theoretically modify the characteristics of the rib cage, with which the contraction of the diaphragm interacts. Third, it can be impossible to locate the nerve, or to do so easily enough to obtain reliable supramaximal stimulation. Because of these difficulties, maintaining a constant symmetric maximal stimulus may need repetitive ES, which in itself can increase twitch pressure by potentiation or the staircase phenomenon (91, 92) (see also TWITCH POTENTIATION).

The technical expertise required for effective ES may, thus, be a source of variability in research studies and limit its use in the clinical field, particularly in demanding settings such as the ICU or exercise.

Magnetic Stimulation
Scientific basis.
The ability of magnetic fields to stimulate nervous structures has long been known (93). Magnetic stimulation creates intense and brief magnetic fields, which, unlike electric currents, are only mildly attenuated by natural barriers such as skin and bone. They can therefore reach deep nervous structures, where stimulation is produced in situ by the electrical fields induced by the rapidly changing magnetic fields (Figure 10) . The mechanisms of neural response to magnetic stimulation are different from those of the response to electrical stimulation (94–97), and therefore the results obtained with the two techniques may have different interpretations. Nevertheless, magnetic stimulation has the advantage of being relatively painless and is thus easily applicable in the clinical setting. Several review articles were discussed by Chokroverty (98).

View larger version (36K): [in this window] [in a new window]   Figure 10. Schematic representation of the principle of magnetic stimulation. The electric current produced by the charging circuit is stored in capacitors. Switching on the trigger circuit results in a sudden pulse of electric current in the coil of wire held in contact with the patient. The intensity of this pulse of current can be modulated (from 0 to 100% of maximal intensity). A pulsed magnetic field orthogonal to the current flowing through the coil is produced. This magnetic field is able to penetrate body tissues such as skin or bone with little attenuation. It in turn induces secondary electric currents of low intensity in deep structures. If such a structure, for example, the cerebral cortex or the trunk of a peripheral nerve, lies at a tangent to the secondary electric currents, it is depolarized at a point that depends on the local geometry and on the intensity of the current. The intensity of the magnetic field induced within the tissues decreases with distance. The maximum magnetic field intensity produced by modern stimulators is around 2.5 Tesla.

View larger version (19K): [in this window] [in a new window]   Figure 11. Technique for cervical magnetic stimulation (CMS). Top: The usual technique for CMS. The subject being seated, a circular coil of approximately 90 mm in diameter attached to a magnetic stimulator is centered on the spinous process of the seventh cervical vertebra (C7). The subject is usually asked to bend the neck forward to facilitate contact between the coil and the posterior surface of the neck. In this example, esophageal and gastric pressures (Pes and Pga, respectively) are measured via conventional balloon-catheter systems (see TECHNIQUES FOR PRESSURE MEASUREMENTS). Subtracting Pes from Pga gives transdiaphragmatic pressure (Pdi). Surface electrodes are shown for the assessment of the electromyographic response of the diaphragm to stimulation (EMGdi). Bottom: Sites of nervous stimulation possibly responsible for the diaphragmatic contraction induced by CMS using a conventional 90-mm doughnut-shaped coil. The gray area is a schematic representation of the magnetic field. This can, theoretically, depolarize cervical roots, and also the phrenic nerve itself anteriorly, behind or below the clavicle. Phrenic nerve stimulation is theoretically possible with a circular coil placed anteriorly (lying flat on the upper part of the sternum: anterior magnetic stimulation) or posteriorly but lower (coil held vertical on the upper dorsal vertebral column).

Methodology.
The subject, comfortably seated in a chair, is asked to bend the neck forward slightly. The coil is applied to the back of the neck, its midline coinciding with the axis of the vertebral column (Figure 11). Optimal results are generally obtained with the coil centered around the spinous process of the seventh cervical vertebra (C7), but slightly higher and lower positions should be tried with monitoring of pressure or EMG, although care may be required to obtain satisfactory surface EMG signals. The optimal coil position may vary with the size and neck morphology of the subject. Stimulation intensity is generally set to the maximal output of the stimulator (see SUPRAMAXIMAL STIMULATION).

Several manufacturers provide magnetic stimulators suitable for CMS. High-powered machines, capable of producing magnetic fields of 2–2.5 T with a medium-size circular coil, should be used. Doughnut-shaped coils 90 mm in diameter are particularly suitable for generating bilateral diaphragmatic contractions for the measurement of twitch pressure (100, 107–110).

Advantages.
Cervical magnetic stimulation provides easy bilateral PNS. It is not painful: The subject simply perceives a contraction of neck muscles that provoke an extension movement, and a hiccup-like sensation. Any operator reasonably familiar with medical or physiological tests can obtain reliable results after a brief period of training. The number of stimulations applied during a given CMS session is often lower than with ES, which reduces the risk of potentiation and the staircase phenomenon (see previous passages, and TWITCH POTENTIATION, subsequent section). Location of the nerves is technically easier with CMS. The risk of falsely low results due to difficulty in locating the nerves and other technical problems is lower with CMS than with ES. In addition, because of its sites of action (cervical roots of the phrenic nerve [101, 103] or intramediastinal segment of the phrenic nerve [106]), CMS can activate diaphragm fibers innervated by an accessory or ectopic phrenic nerve (111) that would not be accessed by ES (112).

Disadvantages.
Cervical magnetic stimulation lacks the specificity of ES for the diaphragm, because of coactivation of muscles innervated by cervical roots or the brachial plexus. Interpretation of Pdi,tw by CMS is, therefore, not exactly the same as that of Pdi,tw by ES (see subsequent section). Confirming supramaximal stimulation can sometimes be difficult (see subsequent section). Obtaining a reliable EMGdi signal is difficult with CMS, but technical solutions are available (use of shielded EMG cables, transient muting of the EMG amplifiers, etc.) (113) and modern EMG recorders are now designed to support magnetic stimulation. A reasonable distance should be maintained between the stimulating coil and credit cards, computer disks, and the like.

Other Magnetic Stimulation Techniques
Focal magnetic phrenic nerve stimulation.
Small figure of eight- shaped magnetic coils can be used for focal stimulation (focal MS) of the phrenic nerve in the neck unilaterally or bilaterally, at the same point as stimulation by ES (114, 115). Bilateral focal MS is easily applied by an operator standing in front of the subject and gives values for Pdi,tw and the Pga,tw/Pes,tw ratio that are close to ES (115), thus avoiding any problems associated with stimulating upper trunk muscles (see subsequent section). This technique could make bilateral PNS easier in supine patients, as in the ICU, because for ES the operator has to stand behind the patient and for CMS the subject's neck has to lie over the coil, which may be uncomfortable and impede optimal positioning. Unilateral focal MS may allow assessment of the mechanical properties of one hemidiaphragm alone (87, 114, 116).

Anterior magnetic stimulation.
The possibility of evoking a bilateral diaphragm EMG response through anterior magnetic stimulation (antMS) with a 90-mm circular coil similar to that used for CMS, placed flat over the upper part of the sternum, has been described (106). Anterior magnetic stimulation is potentially a simple technique also applicable to supine subjects in difficult settings, but pressure responses remain to be evaluated.

Diaphragmatic Response to Phrenic Nerve Stimulation
Diaphragmatic response to PNS would ideally be measured as work or power. However, length changes and velocity of shortening are invariably ignored and the focus has been on assessing diaphragm force development, either by measurement of pressure, or sound (phonomyography).

Pressure responses to PNS (twitches) are widely used to study diaphragm contraction. They depend not only on diaphragm properties, but also on the load the diaphragm acts against, as for any muscle. This load depends on the mechanical characteristics of the rib cage and abdominal wall (see TECHNIQUES FOR PRESSURE MEASUREMENTS).

Measurement of the sounds created by muscle contraction can now be quantified by phonomyography. At present this is a research tool, but it has considerable promise as it is technically easy and noninvasive (117).

Transdiaphragmatic pressure.
In response to PNS, Pdi rapidly rises to a peak, and then decreases exponentially to its baseline value (Figure 12) to give a characteristic Pdi,tw. The time-to-peak and its first time derivative (rate of rise, dp/dt) depend on several factors, including previous muscle shortening (e.g., increase in lung volume). The amplitude of the twitch reflects the transformation of diaphragm force into pressure and depends on diaphragm strength and contractile properties as well as rib cage and abdominal wall compliance. The dynamics of relaxation of the twitch can be described by the time necessary to reach a Pdi value of 50% of the peak (half-relaxation time) or by the time constant () of an exponential fitted to the pressure–time relationship (87, 118) (see RELAXATION RATE in Section 5 of this Statement).

View larger version (13K): [in this window] [in a new window]   Figure 12. Typical pressure tracings in response to phrenic nerve stimulation. Traces A to C show, respectively, the esophageal pressure (Pes), gastric pressure (Pga), and transdiaphragmatic pressure (Pdi) responses to bilateral, supramaximal, electrical stimulation of the phrenic nerve in the neck, in a patient with COPD (hence the relatively low amplitudes). On the Pdi trace (C) are indicated some indexes often used to describe quantitatively the twitch response: (1) Pdi,tw is the amplitude of the response from baseline to peak; it is the result of the interaction of diaphragm contraction with the rib cage and the abdomen; although not a direct measure of diaphragm intrinsic contractile properties, it is related to diaphragm strength and can be used to characterize it if all other intervening factors are otherwise kept identical (e.g., lung volume, thoracic geometry, rib cage and abdomen compliance, diaphragm state of activation, etc.); (2) ttp and 1/2rt are the time-to-peak and half-relaxation time, respectively; these indexes are used to characterize the dynamics of diaphragm contraction, and are influenced, for example, by muscle shortening or fatigue; and (3) is the time constant of an exponential function fitted to the after-peak decline in Pdi (often referred to as the relaxation time constant); it is influenced by diaphragm intrinsic properties and, for example, is prolonged by fatigue. The trace in D illustrates the similarity in shape, time dynamics, and amplitude in the Pes twitch (thin line) and the mouth pressure (Pmo) twitch (thick line) to phrenic nerve stimulation, in a normal healthy volunteer.

Although there are not yet enough data to propose a precise technique to measure Pmo,tw, the following recommendations seem reasonable. Stimulation should be attempted at relaxed FRC when respiratory system recoil pressure is ordinarily zero. When PEEPi is present, the twitch amplitude should be measured starting at the PEEPi level. If a supramaximal stimulation is obtained, the data can be retained, if time to peak tension is normal. If it is prolonged with low amplitude and prolonged relaxation, then abnormal pressure transmission (probably due to glottic closure) should be first suspected, and stimulation should be repeated during a mild expiratory effort against an occluded mouthpiece.

Advantages.
The principal advantage of Pmo,tw is its simplicity and ease of use. Thus, portable Pmo or Psn devices (28) could probably be adapted for combination with CMS as a simple screening test.

Disadvantages.
The main disadvantage of Pmo,tw is in ensuring the adequacy of pressure transmission from the alveoli to the mouth, particularly in airway obstruction. It seems that glottic closure, which may prevent change in Pmo, is particularly frequent with CMS, although it can occur with ES as well. A technique such as a mild inspiratory effort at FRC (120) or an expiratory effort (110) not only makes the procedure more complicated, but it also changes the meaning of the observed results. Indeed, central nervous system activation and lung volume influence the pressure response to PNS (see CONFOUNDING FACTORS). With CMS, Pmo,tw can be the product of diaphragm contraction but also of neck muscle contraction. The importance of this confounding factor remains to be studied in detail (see CONFOUNDING FACTORS).

Esophageal Pressure
The measurement of esophageal pressure alone in response to PNS provides an intermediate approach between the measurement of Pdi and Pmo. Measuring Pes,tw is less simple than measuring Pmo,tw, but the problem of incomplete pressure equilibration due to glottic closure or airways time constant does not exist. Normal values for Pes,tw are by definition similar to values for Pmo,tw.

Comparison between Transcutaneous Electrical Phrenic Nerve Stimulation and Cervical Magnetic Stimulation
Practical aspects.
The practical aspects of ES and CMS are described in previous sections. In summary:

1. ES is the original method for generating an isolated contraction of the diaphragm, but for the operator is difficult to master.
   
2. CMS is easier and faster to apply, with a lower risk of false results due to technical problems. It is better tolerated by the subject. There is some cocontraction of the upper rib cage and neck muscles, stiffening the rib cage, so that Pdi may be greater than with ES.
   

Physiological aspects.
The two techniques are comparable with respect to reproducibility (similar within-occasion and between-occasion coefficients of variation) (100, 107) and the time characteristics of the Pdi twitches are very close. When supramaximal bilateral ES and CMS are compared in the same subjects (107–109) Pdi,tw values measured during CMS appear consistently higher by approximately 20–25% than Pdi,tw measured during ES, the difference being accounted for by more negative Pes values.

Conclusion and perspectives.
Cervical magnetic stimulation and ES do not provide the same physiological information, so that normal values for PNS-related pressures (see APPLICATIONS AND PERSPECTIVES) depend on the technique used. This also means that the results of CMS and ES may be affected differently in diseases affecting both diaphragm and rib cage muscles. The possibility of focused phrenic nerve magnetic stimulation in the neck with small figure-of-eight coils bilaterally (114, 115) will probably reconcile the physiological need for pure diaphragm contraction and the clinical need for simplicity. CMS and other techniques of magnetic stimulation of the phrenic nerve, being easier to use than ES, should then overcome the limitations of ES for large series, exercise, ICU, or intraoperative studies.

Confounding Factors
Supramaximal stimulation.
To provide valid information about the maximal strength of the whole diaphragm, PNS should be bilateral and supramaximal.

Although PNS should be supramaximal if Ptw is to accurately reflect maximal diaphragm mechanical output, this is not necessary when PNS is used to study phrenic conduction time (see Section 3 of this Statement). Failure to achieve supramaximality leads to underestimation of diaphragm mechanical output, overestimation of central drive when using twitch occlusion (see PARTICULAR TECHNIQUES), and variability. The "gold standard" to achieve a reasonable degree of certainty about the supramaximality of PNS is to establish a recruitment curve using the EMGdi, and stimulation is maximal when there is no further increase in EMGdi in response to an increase in intensity. Increasing stimulus intensity by a further 10–20% provides a reasonable safety margin that compensates for slight changes in the quality of the stimulus. With CMS, it can be difficult to reach a clear plateau in amplitude of the action potential with intensity, but the peak-to-peak amplitudes of the action potentials produced by CMS at the maximal intensity of stimulation with a 2.5-T magnet are not different from the peak-to-peak amplitudes produced by supramaximal bilateral ES (109). The increasing power of stimulators may help reduce this problem in the future.

Lung volume.
Lung volume has a major influence on the ability of the diaphragm to produce pressure, during voluntary static or dynamic maneuvers (13, 36, 122–128) and in response to PNS (83, 84, 117, 119, 129–134). This is a result of the inverse relationships of length with force in skeletal muscles, and of lung volume with diaphragm length (36, 69, 125). Pdi,tw decreases as lung volume increases, with a prominent reduction in Pes,tw that is close to zero at TLC (83, 129–131, 134–136) (Figure 13) . Isovolume changes in rib cage and abdominal configuration also influence Pdi,tw (83, 84, 125).

View larger version (30K): [in this window] [in a new window]   Figure 13. The effects of lung volume on twitch pressure. Shown is the marked decrease in the amplitude of transdiaphragmatic pressure (Pdi,tw) during an acute inflation from functional residual capacity to total lung capacity, both in normal volunteers (solid circles) and in patients with preexisting hyperinflation impairing baseline diaphragm efficacy (open circles). This reduction in Pdi with volume is mainly due to a reduction in the esophageal pressure (Pes) component of the twitch, which becomes very close to zero at TLC in normal subjects.

How sensitive to changes in lung volume is the pressure response to PNS? Between FRC and TLC, Pdi,tw and Pmo,tw decrease by approximately 3%/100 ml (83, 84, 119, 130, 132), and between RV and FRC by approximately 5%/100 ml (83, 128). These changes appear to be reduced if care is taken to avoid potentiation (129) and may be less in the elderly (131, 134).

Lung volume, and if possible rib cage/abdominal configuration, should be carefully controlled when assessing PNS pressures in research settings. When PNS is repeated in patients with labile lung volumes, FRC should be measured on the day of the study. Assessing lung volume may be less crucial for clinical assessment, recognizing that a change in Pdi,tw or Pmo,tw can reflect changes in diaphragm properties, or lung volume, or both.

Twitch potentiation.
A transient increase in the contractility of a skeletal muscle follows its contraction. This phenomenon is called potentiation (143, 144).

The possibility of twitch potentiation should be taken into account when interpreting studies involving PNS. A period of quiet breathing, e.g., 15 min, should be allowed before recording diaphragm twitches, particularly if maximal maneuvers or sniffs are performed beforehand (145–147).

Hypertrophy of neck muscles.
When there is a bilateral paralysis, Pes,tw and Pdi,tw during ES are zero. With CMS, coactivated neck muscles can, theoretically, produce some degree of Pes,tw during CMS. This effect may be small in most subjects (148), but could be larger in patients with hypertrophied inspiratory neck muscles (149).

Particular Techniques
Twitch occlusion
Scientific basis. The degree of activation of a skeletal muscle during voluntary efforts can be assessed by use of the twitch occlusion technique. Twitches produced by electrical stimulation of a parent nerve are superimposed on a voluntary isometric contraction of the muscle (150). The amplitude of the twitch decreases linearly as the strength of the underlying contraction increases. When the activation is maximal it completely suppresses the twitch (150–153) (Figure 14) . It is usual to compare the amplitude of the interpolated twitch with that of the fully potentiated twitch performed on the relaxed muscle.

View larger version (23K): [in this window] [in a new window]   Figure 14. Twitch occlusion technique. Top: Procedure that can be used to study the effects of a voluntary diaphragmatic contraction (Pdi,vol) on the response to phrenic nerve stimulation (Pdi,tw). Pdi is displayed on an oscilloscope visible to the subject and the operator. The subject is asked to perform stepwise graded contractions, guided by the Pdi trace, and to sustain several levels of Pdi for a few seconds. The operator superimposes one or more stimulations during each sustained contraction. Bottom: two examples of twitch occlusion procedures. In both cases, Pdi,tw decreases linearly with Pdi,vol, according to Pdi,tw = a - b Pdi,vol. The left panel illustrates a subject capable of maximally activating the diaphragm: the subject can produce a voluntary contraction that is associated with complete absence of Pdi,tw. The right panel illustrates a subject not capable of maximal contraction: Pdi,max can be estimated by extrapolating the Pdi,tw–Pdi,vol relationship to the x axis, and is equal to the ratio of the intercept of this relationship to its slope (Pdi,max = a/b, arrow).

Main results and applications.
Superimposed Pdi,tw decreases linearly with the degree of underlying voluntary Pdi (Pdi,vol) (Figure 14) according to:

The y intercept (a) of Equation 1 closely matches the value of Pdi,tw obtained at relaxed FRC, and its x intercept closely matches Pdi,max. The a/b ratio corresponds to the diaphragm twitch-to-tetanus ratio, which is 0.20–0.25 in most studies, close to the twitch-to-tetanus ratio of skeletal muscles in mammals (157), giving credibility to the technique.

From the twitch occlusion technique, it has been possible to:

1. Assess the degree of central activation associated with voluntary diaphragm contraction (88, 158).
   
2. Discriminate between the central and peripheral components of diaphragm fatigue or weakness (88, 159, 160) (see TYPES OF FATIGUE in Section 5 of this Statement).
   
3. Detect central inhibition of the drive to breathe (131, 161, 162).
   
4. Estimate Pdi,max from submaximal efforts (56).
   

Methodology.
The technique by which bilateral supramaximal PNS is to be performed should be that established for ES (56, 88, 120, 131, 154, 155, 160, 161, 163–167) or CMS (108). A visual feedback of Pdi is provided to the subject and the operator on an oscilloscope or computer screen. A standard procedure is as follows. First, Pdi,max is determined. Then, the subject is asked to produce, in a stepwise manner, fractions of Pdi,max previously marked on the screen of the oscilloscope. While a given step is briefly sustained, one or a few stimuli are delivered so that data for Equation 1 can be built up. To assess the degree of central activation a single stimulus over any inspiratory effort followed by a stimulus in relaxed condition may be sufficient (88).

Advantages.
Twitch occlusion allows an investigator to separate central from peripheral weakness or fatigue of the diaphragm (80).

Disadvantages.
The twitch occlusion technique is restricted by the difficulties inherent in ES and Pdi measurement. The consistency of the stimulus delivered to the nerves becomes increasingly difficult to maintain as neck muscles are recruited during intense inspiratory maneuvers, although CMS (109) or Pmo (120) could help. When graded voluntary Pdi maneuvers are performed, neck muscles often stay relaxed during low-intensity diaphragm contractions, but are coactivated during high-intensity contractions (70% of Pdi,max and above) (56), which may decrease rib cage distortability. During twitch occlusion from relaxed conditions to maximal effort, diaphragm contraction will interact with a distortable rib cage at low Pdi,vol values, and with a much stiffer rib cage at high Pdi,vol values, complicating the results. This problem may disappear with CMS, because it tends to stabilize the upper rib cage at all levels of Pdi,vol (109). The impact of twitch potentiation on the twitch occlusion procedure is not known. Theoretically, potentiation of Pdi,tw would lead to an underestimate of the central component.

Force–frequency curves.
When stimulation frequency increases, the mechanical output of the stimulated muscle increases up to a plateau (tetanic contraction). Force–frequency curves contain much information about skeletal muscle contractility, and reflect the type and severity of muscle fatigue.

Human diaphragm force–frequency (or, rather, pressure–frequency) characteristics in vivo have been described with unilateral PNS (81, 168, 169) and bilateral PNS (116, 170–172), in a limited number of highly motivated subjects. Despite their interest, data remain scarce, because the studies are difficult. First, sequences of supramaximal stimuli are painful and can barely be tolerated, even unilaterally. Second, maintaining adequate sustained supramaximal PNS is demanding, especially as uncomfortable spread of the stimulus to the brachial plexus becomes almost unavoidable with repeated stimuli. Therefore, the use of pressure–frequency curves appears limited and cannot reasonably be proposed for clinical purposes or even for patient-based research. An alternative is to generate a surrogate force–frequency curve using paired phrenic nerve stimuli (173). This approach is acceptable to naive elderly subjects (174) and patients (175).

Normal Values
Values for Pdi,tw or Pmo,tw in normal subjects can be found in more than 40 published studies, irrespective of the technique used (10, 56, 65, 83–85, 88–90, 100, 107, 110, 115, 116, 118–120, 129, 131, 132, 134, 145, 146, 155, 160, 161, 165–167, 170–173, 175–190) (Table 4). Normal young (20–35 years) male individuals provide the vast majority of the data.

Amplitude of bilateral twitch transdiaphragmatic pressure.
Assuming a correct technique, at FRC, Pdi,tw with ES should be above 15 cm H₂O and Pdi,tw with CMS should be above 20 cm H₂O.

A Pdi,tw below 15 cm H₂O, whatever the PNS technique, should raise high suspicion of diaphragm dysfunction (110, 114, 131, 179, 187, 190–196).

Influence of age, sex, and other characteristics.
As with voluntary pressures (26, 128, 197), normal Pdi,tw tends to be lower in women than in men and tends to decrease with age (120, 131, 182, 190). The influence of other factors such as height, race, fitness, etc., is unknown, although data suggest that baseline Pdi,tw in highly fit subjects is not different from normal subjects (185), but with a better resistance to maximal exercise-induced fatigue.

Other characteristics of the twitch transdiaphragmatic pressure response to phrenic nerve stimulation.
The ratio of Pes,tw to Pdi,tw in normal individuals is usually between 0.35 and 0.55.

Amplitude of twitch transdiaphragmatic pressure.
Available data are still scarce, but a value of Pmo,tw during CMS less negative than -11 cm H₂O should probably prompt more detailed investigation (110). Pmo,tw during ES tends to be lower, and a value more negative than -8 cm H₂O with this technique is probably normal (119).

Applications and Perspectives
The use of PNS-derived pressures to study the mechanical action of the diaphragm assumes that stimulation is bilateral and supramaximal, and that care is taken to control for lung volume and twitch potentiation.

Research applications.
Bilateral ES is an important tool in human diaphragm research, used to study the properties of the diaphragm and the mechanisms of its fatigue independently of volitional influences. The twitch occlusion technique, as the only means to separate the peripheral and central components of diaphragm dysfunction, is also an important, if complex, research tool. The use of paired stimuli could facilitate research on the frequency characteristics of diaphragm fatigue (174).

Cervical magnetic stimulation provides slightly different information from ES, mainly because of rib cage muscle coactivation. However, its simplicity for the subject and the operator makes it a valuable tool for clinical research, especially in difficult settings, such as the ICU, or when repeated studies are needed, such as the evaluation of therapeutic interventions.

Clinical applications.
Contraindications.
There are virtually no contraindications to ES and MS, but their use requires some precautions. MS should not be performed in patients with a cardiac pacemaker. Patients with orthopedic implants, even metallic ones, can be studied with MS (e.g., candidates for phrenic pacing after high cervical cord injury) (198) after sufficient time for consolidation.

Clinical use.
Pressure responses to PNS play an important part in the clinical evaluation of inspiratory muscle function. Diaphragmatic weakness can be established and quantified with PNS, particularly when voluntary maneuvers are equivocal. The use of MS with Pmo may be an even simpler nonvolitional measure.

The preoperative assessment of patients for possible phrenic pacing after high cervical cord lesions constitutes a particular application. PNS provides information on phrenic nerve conduction time, which is important in making the decision to undertake pacing (198). It also provides an estimate of the degree of diaphragm disuse atrophy, which is an important determinant of the reconditioning strategy (199).

Given that methodological precautions are rigorously respected, PNS is one of the more reproducible respiratory muscle tests, and this makes it suitable for follow-up studies (see PHRENIC NERVE STIMULATION in Section 3 of this Statement).

ABDOMINAL MUSCLE STIMULATION
The abdominal muscles are major contributors to respiration, both through their expiratory action on the rib cage and their mechanical linkage with the diaphragm. Their function can be explored by voluntary maneuvers (see VOLITIONAL TESTS OF RESPIRATORY MUSCLE STRENGTH), with the usual limitations of subjects understanding and cooperation. A nonvolitional test giving information on abdominal muscle mechanical output would, therefore, be of interest.

Contraction of the abdominal muscles can be provoked by their direct electrical stimulation. This technique has been used in humans to study the action of various abdominal muscles on the rib cage (200), and in a study of diaphragm maximal voluntary activation (155). From a therapeutic point of view, its use has been considered to enhance cough in patients with cervical cord injury (201). However, direct electrical stimulation is painful and supramaximality is difficult to achieve. It is also difficult to activate all muscles groups at once.

Contraction of the abdominal muscles can also be provoked by stimulation of their parent nerves and roots (202). Theoretically, this allows supramaximal stimulation (and therefore reproducibility) and, if the stimulus is widespread enough, simultaneous activation of all abdominal muscles. Magnetic stimulation over the vertebral column at the level of the eighth to tenth thoracic vertebra could provide an easy-to-use nonvolitional assessment of abdominal muscle strength and fatigue (202, 203).

CONCLUSION
The purpose of this Section is to describe the tests used to assess respiratory muscle strength. To test strength, pressures can be measured either during voluntary maneuvers or during involuntary contractions, particularly in response to phrenic nerve stimulation.

A. Volitional Tests of Respiratory Muscle Strength: Volitional tests are often simple for patients to perform, but it can be difficult to be certain that a maximum effort has been made. This can lead to difficulty in the interpretation of low results.

1. Maximum Static Inspiratory and Expiratory Pressure

i. PImax and PEmax are commonly used, clinically useful measurements. Some individuals have difficulty with the technique and the interpretation of low results can be problematic.

ii. Maximum static transdiaphragmatic pressure (PI,di,max) provides specific information on diaphragm strength, but can be a difficult maneuver in naive subjects and patients. PI,di,max has a wide normal range and has limited usefulness in clinical practice.

2. Maximum Sniff Pressures: Maximum sniff efforts can be achieved by patients with little practice; sniff pressures are reproducible and have a narrower normal range than static mouth pressures or PI,di,max. Sniff esophageal pressure assesses global inspiratory muscle strength and sniff Pdi is a clinically useful measure of diaphragm strength. Sniff nasal pressure provides a useful noninvasive measure of inspiratory muscle strength and has been validated in patients with neuromuscular disease.

3. Maximum Cough Pressure: Cough gastric pressure is measured as an index of abdominal muscle strength. Pga,co is a useful test to supplement PEmax, particularly in patients unable to perform the PEmax maneuver reliably. To date, few data are available for normal values of Pga,co.

B. Nonvolitional Tests of Respiratory Muscle Strength

1. Phrenic Nerve Stimulation: Phrenic nerve stimulation is specific for the diaphragm and is not influenced by the central nervous system.

i. Electrical phrenic nerve stimulation (ES) can achieve selective supramaximal stimulation of the diaphragm, but requires considerable skill, is sometimes uncomfortable for patients, and is difficult to achieve in some clinical settings (e.g., the ICU).

ii. Magnetic phrenic nerve stimulation (MS) is technically easier for the operator and less uncomfortable for the patients. Cervical magnetic stimulation (CMS) elicits a bilateral diaphragm contraction. CMS is less specific than ES, and coactivates muscles innervated by the brachial plexus. Achieving and confirming supramaximal nerve stimulation can be difficult, and recording the diaphragm EMG can pose problems. Unilateral anterior–lateral MS is more specific than CMS, and results are similar to ES. Unilateral MS allows the investigation of hemidiaphragm function, and bilateral anterior–lateral MS reliably achieves supramaximal stimulation.

iii. Twitch transdiaphragmatic pressure (Pdi,tw) provides an index of diaphragm, or hemidiaphragm, strength. Normal values are available and Pdi,tw is a useful clinical measurement. Twitch mouth pressure (Pmo,tw) can provide a noninvasive measure of diaphragm strength, but inadequate transmission of alveolar pressure to the mouth, in patients with airway obstruction or when there is glottic closure, is a substantial practical problem limiting clinical application.

iv. Pdi,tw is a research technique useful to assess the degree of activation of the diaphragm during voluntary efforts (the technique of twitch occlusion) and Pdi,max can be estimated from submaximal efforts.

2. Abdominal Muscle Stimulation: Magnetic stimulation over the eighth to tenth thoracic vertebrae posteriorally, and the recording of twitch gastric pressure, provide a clinically applicable nonvolitional test of abdominal muscle strength. Data on normal values for twitch gastric pressure are limited.

ABBREVIATIONS
Measures
P Pressure (usually mouth pressure if site not specified, as PImax)

L Length

V Volume

EMG Electromyogram

PMG Phonomyogram

Sites and Modifiers
A, alv Alveolar

ab Abdomen

abw Abdominal wall

ao Airway opening

aw Airway

bs Body surface

di Diaphragm, transdiaphragmatic

es, oes Esophageal

g, ga Gastric

ia Intercostal/accessory muscles

mo Mouth

mus Muscle

nas Nostril, nasal

np Nasopharynx

ph Phrenic

pl Pleural

rc Rib cage

rs Respiratory system (lung and chest wall)

w, cw Chest wall

ant Anterior

post Posterior

E Expiratory

I Inspiratory

Maneuvers
co Cough

max Maximal

sn Sniff

tw Twitch

vol Voluntary

Stimulation Descriptors
ELS Electrical stimulation

MS Magnetic stimulation

Ant MS Anterior magnetic stimulation

CMS Cervical magnetic stimulation

fMS Focal magnetic stimulation

PNS Phrenic nerve stimulation

EMG Electromyogram

PMG Phonomyogram

M-wave EMG response to PNS

Lung Volumes
FRC Functional residual capacity

RV Residual volume

TLC Total lung capacity

VC Vital capacity

General
CNS Central nervous system

HFF High-frequency fatigue

LFF Low-frequency fatigue

MVC Maximal voluntary contractions

SMVC Submaximal voluntary contractions

Principles
Give measure, then site, then maneuver, then descriptor. Thus:

Pes,tw,CMS = twitch esophageal pressure following cervical magnetic stimulation

PE,mo,max = maximal expiratory mouth pressure (usually abbreviated to PEmax)

Pg,co = gastric pressure during a cough

	FOOTNOTES

 
For Abbreviations see page 547.

	REFERENCES

TOP INTRODUCTION Introduction 1. Tests of Overall... REFERENCES 2. Tests of Respiratory... REFERENCES  3. Electrophysiologic Techniques... REFERENCES   4. Tests of Respiratory... REFERENCES    5. Assessment of Respiratory... REFERENCES     6. Assessment of Chest... REFERENCES     8. Tests of Upper... REFERENCES     9. Tests of Respiratory... REFERENCES     10. Assessment of Respiratory... REFERENCES

 

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	3. Electrophysiologic Techniques for the Assessment of Respiratory Muscle Function

TOP INTRODUCTION Introduction 1. Tests of Overall... REFERENCES 2. Tests of Respiratory... REFERENCES  3. Electrophysiologic Techniques... REFERENCES   4. Tests of Respiratory... REFERENCES    5. Assessment of Respiratory... REFERENCES     6. Assessment of Chest... REFERENCES     8. Tests of Upper... REFERENCES     9. Tests of Respiratory... REFERENCES     10. Assessment of Respiratory... REFERENCES

There are two main types of electrophysiologic tests of respiratory muscle function: electromyography and stimulation tests. These tests are interrelated, and they are related also to tests of mechanical action of the respiratory muscles, described elsewhere in this Statement.

ELECTROMYOGRAPHY
Rationale
Electromyography (EMG) is the art of describing myoelectric signals (1), the electrical manifestations of the excitation process elicited by action potentials propagating along muscle fiber membranes. The EMG signal is detected with electrodes, and then amplified, filtered, and displayed on a screen or digitized to facilitate further analysis. Electromyography of respiratory muscles can be used to assess the level and pattern of their activation, so as to detect and diagnose neuromuscular pathology, and, when coupled with tests of mechanical function, to assess the efficacy of the muscles' contractile function (see ELECTROMECHANICAL EFFECTIVENESS in Section 6 of this Statement).

Scientific Basis
Single fiber action potential.
Depolarization of a muscle fiber membrane, caused by the flow of ions across the sarcolemma, generates an electric field outside the muscle fiber, which can be detected by extracellular recording electrodes as voltage changes over time; this voltage transient is known as the action potential. Although the transmembrane potential changes generated by depolarization of a given fiber are always identical in shape and amplitude (the "all or nothing" phenomenon), the shape and amplitude of a recorded action potential depend on factors such as the orientation of the recording electrodes with respect to the active muscle fibers, the distance between the muscle fibers and the electrodes, the filtering properties of the electrodes, and the muscle fiber action potential conduction velocity (2).

In humans, muscle fiber conduction velocity ranges from 2 to 6 m/second (3), depending on passive and active components of the muscle fiber membrane. The passive components (cable properties) include capacitance per unit length (proportional to fiber circumference) and internal resistance (inversely proportional to the square of the fiber diameter). The active components (membrane excitability) depend on ion gradients across the membrane and properties of the ion gating channels, which in turn are influenced by electric field strength, temperature, and chemical milieu (especially pH and Ca²⁺ concentrations). Muscle fiber conduction velocity has been shown to vary with fiber diameter (4), temperature (3), electrolyte gradients across the cell membrane (5), pH (5), and fatigue (1, 6).

Single motor unit action potential.
Each motor unit is composed of a number of individual muscle fibers innervated by a single anterior horn cell. All individual fibers within a motor unit are activated almost simultaneously. The amplitude and shape of the resulting motor unit action potential (MUAP) are influenced not only by all the factors that can affect single fiber action potentials, but also by such factors as the number of fibers within the motor unit, the spatial dispersion of motor unit fibers, differences in length of the motor neuron terminal axons, and possibly fiber-to-fiber differences in action potential conduction velocity (2, 7).

Summation of motor unit signals.
Compound muscle action potentials (CMAPs) represent the summated electrical activity generated by all motor units synchronously activated by nerve stimulation (see subsequent passages). The observed CMAP is influenced by the number of activated motor units, their synchronization, the shape of individual MUAPs, and cancellation of opposite phase potentials.

The interference pattern EMG results from the temporal and spatial summation of asynchronously firing MUAP trains during spontaneous muscle contractions, when individual MUAPs can no longer be distinguished (8). The observed interference pattern EMG is thus a function of the number of active motor units, their firing rates and synchronization, the shapes of their individual MUAPs (in turn dependent on all the factors listed here previously), and cancellation of opposite phase potentials (2, 8).

EMG Equipment
Recording electrodes.
Electromyography signals can be detected as the difference between the signal from an electrode placed on or in the muscle under investigation (active electrode) and the signal from another electrode placed in an electrically silent region ("indifferent" or reference electrode). This electrode arrangement is usually referred to as a monopolar electrode. When the two electrodes connected to a differential amplifier are positioned on or in the same muscle under investigation, the electrode arrangement is usually referred to as bipolar. Optimal EMG signals depend on the use of electrodes with appropriate configuration and fixed geometry, on maintenance of electrode position relative to the muscle, on alignment of the electrodes with respect to fiber direction, on selection of sites with relatively low density of motor end plates, and on avoidance of signal disturbances.

Electrodes can be placed on the skin overlying the neck, the chest wall muscles, or the area of apposition of the diaphragm to the chest wall; they can be swallowed into the esophagus to measure crural diaphragm EMG; or they can be inserted into the respiratory muscle of interest, using needle, wire, or hook electrodes. Selection of an appropriate electrode system requires consideration of advantages and disadvantages specific to the technique and the context of the study (Table 1).

Advantages of surface electrodes are their noninvasive nature and their ability to sample a large number of motor units. For many individual nondiaphragm respiratory muscles, however, their proximity to one another and to nonrespiratory trunk muscles makes surface electrode recordings unreliable. Examples include cross-talk from scalenes and platysma in recordings of sternocleidomastoids (9), from external oblique and pectoralis in recordings of intercostal muscles, and among various abdominal muscles (10, 11). Furthermore, variations in interindividual body habitus, for example, subcutaneous fat tissue or deformity of the chest wall, produce variable muscle-to-electrode filtering effects.

Esophageal electrodes.
Esophageal electrodes are metal electrodes mounted on a catheter, which is inserted via the nose or mouth and positioned with the electrode rings at the level of the crural diaphragm. In adults, the motor innervation zone of the crural diaphragm lies 1–3 cm cephalad to the gastroesophageal junction, with the left side approximately 1 cm cephalad to the right (12).

Esophageal electrode catheters are often equipped with gastric balloons and weights on the proximal end, which anchor them in position when outward traction pulls the gastric balloon snugly against the gastroesophageal junction. This feature may limit motion of the electrodes with respect to the esophagus, but it does not prevent either diaphragm movement relative to the electrodes, or the resulting artifacts (13–16). Motion artifacts are minimized in semistatic contractions.

A more reliable method to reduce electrode positioning artifacts during dynamic maneuvers is continuous optimization of diaphragm-electrode positioning. An electrode array of eight rings mounted 1 cm apart on a catheter is introduced and adjusted to provide optimal EMG activity from the central pair of electrodes (17, 18) (Figure 1A) . A computer program samples all electrodes continuously, and selects the pair closest to the crural diaphragm at any point in the respiratory cycle. Application of a double subtraction technique using the difference between signals obtained from each electrode pair caudal and cranial to the crural diaphragm (19) further enhances the signal-to-noise ratio.

View larger version (34K): [in this window] [in a new window]   Figure 1. (A) Schematic description of the methods used to locate the center of the electrically active region of the diaphragm (EARdi,ctr). Left: Raw signals from each of seven electrode pairs on an esophageal probe. Center: The probe with its eight electrodes. Right: Correlation coefficients for cross-correlation of signals from various pairs of electrodes. The dashed curve is the best fit curve, from which the ERA-di ctr position is calculated. (B) An example of the double subtraction technique. Diaphragm EMG signals from electrode pairs located 10 mm caudal and cephalad to the EAR-di ctr are shown. In this case, the signal from Pair 5 was subtracted from that of Pair 3, resulting in increased signal amplitude. Reprinted by permission from Reference 19.

Intramuscular electrodes: advantages.
Intramuscular electrodes provide relatively selective recordings from nondiaphragm respiratory muscles (9–11, 25–30) with sufficient discrimination of individual motor unit activity to allow evidence of denervation or myopathy to be detected. Whitelaw and Feroah (30) have provided a detailed description of a safe method to record single motor unit activity in intercostal muscles with wire electrodes. A number of investigators have demonstrated techniques for placement of monopolar or bipolar needle electrodes in the human diaphragm, either by a medial subcostal approach (31, 32) or by a lower intercostal approach (33, 34) (Figure 2) , sometimes assisted by real-time ultrasound. Fine wire electrodes for single motor unit recordings have also been implanted in the right hemidiaphragms of humans (13, 35). Although the flexible nature of wire electrodes makes them relatively stable during volume changes of up to 1.5 L around the FRC, artifactual changes in recording conditions occur with larger volume changes (13). Wire implants are often used in upper airway muscle studies (see ELECTROMYOGRAPHY in Section 8 of this Statement).

View larger version (89K): [in this window] [in a new window]   Figure 2. Intercostal approach to placement of an electromyography needle in the diaphragm. The needle is inserted one interspace above the lower costal margin between the anterior axillary and medial clavicular lines. During quiet respiration, the needle passes well away from the visceral pleura. Reprinted by permission from Reference 34.

View larger version (58K): [in this window] [in a new window]   Figure 3. (A) A needle EMG record from a normal diaphragm at 200 milliseconds/division and 200 mV/division (B) The same subject recorded at 10 milliseconds/division and 200 mV/division. Reprinted by permission from Reference 34.

View larger version (38K): [in this window] [in a new window]   Figure 4. (A) Needle EMG of the diaphragm of a patient with porphyric neuropathy, showing a few fibrillation potentials and positive wave potentials, along with QRS complexes (calibration, 10 milliseconds/division and 100 mV/division). (B) Needle EMG of the same patient 4 weeks later, showing increased numbers of positive sharp waves and fibrillation. Reprinted by permission from Reference 34.

For simple measurements of motor latencies or CMAP amplitudes, the data display can be as simple as a storage oscilloscope equipped with a camera. A more versatile system, essential for frequency domain measurements, is a computer with an analog-to-digital converter. Because in digitally sampled signals only spectral components of frequencies lower than half the sampling frequency can be observed (the Nyqvist theorem), the sampling frequency should be chosen accordingly.

To provide an analog signal proportional to "average" EMG activity at any point in time, many investigators subject the raw EMG signal to rectification and "leaky" integration. Unless sophisticated analog gating and/or filtering techniques are employed, however, the effects of multiple artifacts detailed in the following sections limit this technique to providing only a crude estimation of the level of muscle activation.

Data Analysis
Time domain EMG analysis.
Time domain EMG analysis represents the electrical activity of the muscles as a function of time. At low levels of contraction, isolated MUAPs can be distinguished and analyzed by such time domain indices as signal amplitude and different types of integrated EMG, including full wave rectified and averaged signal (FRA) and root mean square of the signal (RMS) (36), all of which increase as a function of the number of motor fibers in the unit. Frequency-related indices, such as rise time and duration, can also be measured (36, 37); these are influenced more by action potential conduction velocity and the width of the innervation zone than by the size of the motor unit.

With increasing levels of contraction, more motor units are recruited, and the firing rate increases. The resulting interference pattern EMG can be analyzed by indices such as amplitude, RMS, and FRA, and by frequency-related indices such as zero crossing distance and turn-point distance (36).

Frequency domain analysis.
Frequency domain analysis is a technique to express EMG power as a function of frequency. EMG power is intimately related to its frequency characteristics (8), and frequency characteristics in turn are related to muscle membrane conduction velocity, to filtering properties of the electrodes, to muscle–electrode distances, and to noise (36). Frequency domain analysis greatly simplifies the evaluation of all of these factors, which are difficult to evaluate in the time domain.

The relative contributions of high and low frequencies to EMG signals can be estimated crudely by splitting the signal, filtering the signal with different bandpass filters, integrating the output of each bandpass filter, and comparing the two integrals, to yield a ratio of high-frequency power (e.g., 130–250 Hz) to low-frequency power (e.g., 30–50 Hz), the H/L ratio (38). More useful information can be obtained by power spectral analysis, for which a "window" of time domain EMG data is digitized and subjected to a computerized fast Fourier transform. The fast Fourier transform components are squared and their products are calculated, giving the power spectrum, which graphs the power of the signal as a function of frequency (Figure 5) . To avoid artifactual overestimation of high-frequency content, it is necessary to condition the window of data by tapering its amplitude at the beginning and end of the window or by replacing all data before the first and after the last zero crossing with zeros. These "shaping" processes lead to a slight underestimation of high-frequency content of the EMG (39).

View larger version (48K): [in this window] [in a new window]   Figure 5. Time and frequency domain characteristics of diaphragm EMG signals obtained with bipolar esophageal electrodes positioned near a region with low density of motor end-plates and aligned in the direction of diaphragm fibers. Left: Raw EMG and computed power spectrum from a pair of electrodes with a 10-mm interelectrode distance. Right (top and bottom): Signals derived at the same time from the same region using electrodes with a 5-mm interelectrode distance. Right (middle): On the left is shown a cross-correlogram obtained from the successive cross-correlations at various time delays between EMG signals obtained with a 5-mm interelectrode distance; on the right is shown two motor unit action potentials (MUAPs) obtained from the two electrodes pairs with a 5-mm interelectrode distance. Reprinted by permission from Reference 46.

where P is power density, f is frequency, i is the index over which the power density product is summed, i = 0 is the direct current component, and i_max is the index associated with the highest frequency in the spectrum.

The spectral moment of zero order (M₀) and the root mean square (RMS = M₀^1/2/p, where p is the number of points in the sample) are indices of total EMG power. Theoretically, RMS reflects the force output of the muscle (8). However, both M₀ and RMS are influenced by a number of other parameters, especially conduction velocity (8). In applications in which the power spectrum is expected to shift, as in fatigue, the first-order spectral moment (M₁) may be a more useful index of muscle activation, because it is not affected by changes in action potential conduction velocity (36). Quantification of the distribution of power in the spectrum can be obtained by calculating the center frequency (f_c = M₁/M₀), also known as the mean or centroid frequency. Figure 5 shows how EMG signal power spectra are influenced by interelectrode distance.

Artifacts
Filter effects.
Muscle-to-electrode distance.
Increasing muscle-to-electrode distance results in reduced signal amplitude with relatively larger attenuation of high- than low-frequency power, so that the relative distribution of power in the spectrum is altered and f_c is reduced (1, 14–17, 40) (Figure 6) .

View larger version (22K): [in this window] [in a new window]   Figure 6. The influence of esophageal electrode positioning on diaphragm EMG center frequency (fc) (left axis; circles) and root mean square (RMS) (right axis; squares). Solid symbols indicate experimental data, whereas open symbols indicate computer-simulated power spectra. The "0" on the x axis indicates the center of the electrically active region (source). RMS was lowest at the electrode pair positioned directly over the source (due to the cancellation effect of a bipolar electrode). Caudal and cephalad to the source, RMS increased progressively to maxima at approximately 10 mm from the source in either direction. fc was maximal at the electrode pair directly over the source, hence less high frequency is filtered by the electrode being closer to the muscle. Reprinted by permission from Reference 46.

Signal disturbances.
Electrode motion-induced artifacts.
Movement of the electrode or a change in the pressure on the electrode results in a redistribution of the charges in the resistive–capacitive interface between the electrode and the tissues, causing relatively large amplitude artifacts with low frequency (mostly below 20–25 Hz) (39, 42). Most of the motion artifact can be filtered out with high-pass filters. However, some EMG power occurs at frequencies below 25 Hz, and even the most efficient filter attenuates some of the power above its cutoff frequency. Thus, high-pass filtration inevitably leads to loss of low-frequency power from the EMG signal. When power spectrum analysis is applied, the power related to electrode movement can be reduced (42) or replaced by an extrapolation of the diaphragm EMG power to those frequencies (39).

Noise.
Background noise, signals of unidentifiable origin, can be assumed to have constant power density over the frequency region of interest in EMG recordings. On the basis of this assumption, the noise component of the signal-to-noise ratio is usually estimated from power density values obtained in the uppermost frequency range of the EMG power spectrum (39, 43, 44). Noise originating from modern electrophysiologic instruments is not usually a problem, but ancillary equipment, such as pressure or motion sensors, pumps, or respirators, may introduce noise in various frequency ranges.

Disturbances from power lines.
Sinusoidal alternating currents (ACs) originating from power lines can usually be reduced to a negligible level by proper shielding of electrode cables and connections, by using amplifiers with high common mode rejection ratio, and by connecting all instruments to the same ground point. Residual power line disturbances can be filtered out with "notch filters," or, alternatively, the power of the affected frequency and its harmonics can be excluded in power spectral analysis.

Potential artifactual influences of physiologic origin.
Cross-talk signals.
These are signals originating from muscles other than the muscle being investigated. The best-described source of cross-talk is electrical activity from the heart (EKG). Esophageal recordings of diaphragm EMG are particularly susceptible to cardiac cross-talk, which provides a signal with some 10 times the power of the diaphragm EMG but with a much lower f_c (39, 42). For measurements of stimulation-elicited CMAPs, EKG artifacts are relatively easy to avoid by triggering the stimulus from the QRS complex with an appropriate delay. Alternatively, any record visibly superimposed on the QRS complex can simply be discarded.

For time domain analyses over long periods of time or for power spectral analyses, EKG artifacts pose a significant problem. Heart rates often change, as, for example, with inspiration and with exercise. The frequency content of the EKG is lower than that of EMG activity, but there is considerable overlap (39, 43). Thus, if the high-pass filter is set high enough to eliminate most of the EKG activity, it will also eliminate much of the EMG activity. When EMG frequency content might be shifting toward lower frequencies, as during increasing muscle effort, excessive high-pass filtration will result in spurious reductions in measured RMS. Methods to eliminate the cardiac activity from esophageal recordings of diaphragm EMG by template subtraction (45) have been proposed. However, because the amplitude and shape of the electrocardiogram change with changes in lung volume, the safest method to avoid cardiac influences on diaphragm EMG signals still appears to be selection of signal segments that are free of cardiac activity (39).

Another source of cross-talk in esophageal recordings of diaphragm EMG is esophageal peristalsis (39). The esophageal peristalsis signals show a relatively large amplitude and relatively low-frequency content. In general, signal segments contaminated by esophageal peristalsis, usually easily identified as strong, slow esophageal pressure waves, should be excluded from analysis.

Other examples of cross-talk sources include contamination of diaphragm EMG data recorded from electrodes on the lower rib cage with abdominal or intercostal muscle activity and contamination of intercostal muscle EMGs by interference from pectorals, abdominals, or diaphragm (46).

Innervation zones.
Electrodes positioned close to or over an innervation zone (a region with a high density of motor end plates) produce complex interference patterns, because the action potentials elicited by firing of an individual motor unit may propagate in opposite directions relative to the electrodes (2, 47, 48). Characteristically, there is reduced total power and increased high-frequency content (49). This effect is maximal when bipolar electrodes are oriented parallel to fiber direction; esophageal electrodes, which are arranged approximately perpendicular to fibers, are less susceptible (18).

Influence of changes in muscle length or chest wall configuration.
Changes in chest wall configuration systematically affect the amplitude and frequency content of evoked CMAPs measured with chest surface or esophageal electrodes (13, 50). With spontaneous EMG activity, artifact-free signals recorded from esophageal electrodes are not systematically affected by changes in chest wall configuration (17, 18, 25, 50, 51). Because conduction velocity is not significantly affected by muscle length (52), most of the chest wall configuration effects on EMG are probably due to muscle-to-electrode distance or orientation changes.

Influence of changes in muscle temperature.
Muscle temperature increases during exercise, because of the increase in blood flow to the muscle (53, 54), and metabolic heat production (55). Because the propagation velocity of the muscle fiber action potential is correlated with temperature (56, 57), EMG frequency content must also be temperature dependent. No method for control of or correction for temperature in recordings of respiratory muscles has yet been described.

Applications
See Table 2.

Bolton (34) has pointed out that the relatively high-frequency, low-amplitude potentials of the normal diaphragm are often difficult to differentiate from myopathic potentials. Nevertheless, several neuromuscular diseases present primarily with respiratory muscle weakness; as experience is gained with single fiber and motor unit analysis of respiratory muscles, these techniques applied to respiratory muscles may provide the earliest evidence of the neuro- or myopathic process.

Interference pattern signal.
The interference pattern EMG (raw EMG from surface electrodes) of respiratory muscles is useful for the determination of the timing and level of muscle activation during respiratory activities. Thus, EMGs can help to determine which of the many respiratory muscles are active in various phases of respiration, in various body positions, in various states of consciousness, and in various clinical conditions (see ELECTROMYOGRAPHY in Section 8 of this Statement). Specifically, the absence of voluntary or involuntary EMG activity can be used as evidence of paralysis of specific respiratory muscles. EMGs can also help to quantify the respiratory muscle activation responses to loaded breathing and to CO₂-stimulated breathing or to monitor and control mechanical ventilation (58, 59). Furthermore, when related to pressure or force developed by respiratory muscles, EMGs can help to assess the electromechanical "efficiency" of respiratory muscle function (see ELECTROMECHANICAL EFFECTIVENESS in Section 6 of this Statement).

Interindividual comparisons of absolute FRA or RMS values do not meaningfully reflect respiratory drive, because of varying filtering influences of electrode placement relative to the contracting muscles and/or anatomic differences between subjects, for example, the amount and type of interlaying tissue. However, changes in these indices in response to interventions such as changes in inspired CO₂ concentration, loaded breathing, exercise, states of consciousness, drugs, or other influences, reflect changing motor output of the central nervous system (CNS) to respiratory muscles. Because some respiratory muscles are silent during quiet breathing, it is not practical to normalize respiratory muscle EMG activity to that observed during resting tidal breathing. It is often more practical to normalize EMG activity to that observed during sniff inhalations or maximal inspiratory efforts (22).

The interference pattern EMG of respiratory muscles may also be useful for the assessment of respiratory muscle fatigue (see ELECTROMYOGRAPHY in Section 5 of this Statement). Localized muscle fatigue is accompanied by a reduction in muscle fiber action potential conduction velocity (1), which is reflected in the diaphragm EMG power spectrum as a shift toward lower frequencies (41, 52). This "spectral shift" is most commonly quantified as a reduction in f_c. Spectral shifts have been detected in healthy subjects during inspiratory resistive breathing (38, 60), in patients with weak inspiratory muscles constrained to breathe with prolonged inspiratory duty cycles (61) or with exertion-induced inspiratory muscle overload (62), and in patients with chronic obstructive pulmonary disease during exertion (43), and they are associated with changes in respiratory effort sensation (63). The EMG frequency spectrum is often influenced by other factors, such as the signal-to-noise ratio, electrode position, and recruitment of muscles that potentially contribute to cross-talk. Technical factors affecting the EMG power spectrum must always be taken into account before any physiologic interpretations of a spectral shift can be made (1, 15–19, 41–48).

STIMULATION TESTS
Rationale
Peripheral nerve, spinal, or cortical stimulation, either by implanted electrodes (for peripheral nerves) or by externally applied electric or magnetic fields, elicit relatively synchronized activation of motor units at reproducible and predictable levels. The resulting compound action potentials and subsequent muscle contraction allow for measurement of the efficiency of neural and neuromuscular transmission. The muscle responses to stimulation are discussed in PHRENIC NERVE STIMULATION in Section 2 of this Statement.

Scientific Basis
For practical purposes, human respiratory motor nerves are not accessible over a sufficient length to permit phrenic or other respiratory nerve conduction velocities to be measured. However, motor latency can be measured. Included in the latency are the times required for (1) initiation of action potentials in the axons, (2) rapid saltatory conduction through myelinated axons, (3) slow conduction along the thinner terminal twigs, and (4) chemical transmission across the neuromuscular junctions.

Equipment
Nerve stimulation.
Stimulation of respiratory nerves can be accomplished with electrical or magnetic stimulators (Table 3). The former are less expensive, less cumbersome, more rugged, and more precisely controllable; the latter are easier to apply and less painful for patients. For electrical stimulation, the phrenic nerve is stimulated transcutaneously by surface electrodes at the posterior border of the sternomastoid, or with implanted needle, wire, or hook electrodes. The phrenic nerve(s) can also be stimulated magnetically, via a dorsal cervical approach, which stimulates the lower cervical nerve roots; via an anterior presternal approach, which stimulates both phrenic nerves; or, using one or two figure-of-eight coils, unilaterally or bilaterally over the anterior neck to stimulate one or both phrenic nerves.

In most cases, it is important to be sure that the delivered stimulus is strong enough to activate maximally all motor units in the muscle of interest. To that end, elicited CMAP amplitude is measured as a function of stimulus intensity, and, for subsequent measurements, stimulus intensity is set to be supramaximal, 20–50% above that required for maximal response. During long experiments, it should be regularly verified that stimulus intensity is supramaximal.

Cortical stimulation.
It is now possible to stimulate cortical and subcortical neural pathways in human subjects, using high-voltage (up to 1,500 V) electrical stimulators (69) and magnetic stimulators (up to 3.0 T) (70). Electrical stimulation of the cortex requires saline-soaked gauze pads (or silver–silver chloride electrodes) on the scalp with the anode positioned over the relevant region of the motor cortex. For the diaphragm and intercostal muscles, the optimal site is close to the midline at or just anterior to the vertex (71). The cathode can either be a single electrode 6–8 cm anterior to the anode, a ring of electrodes placed around the scalp, or an electrode several centimeters lateral to the anode at the vertex. Commercially available magnetic stimulation coils consist of several circular coils in a single housing (usually > 10 cm in diameter) positioned (usually tangentially) with their edges close to the scalp region of interest. Positioning of large circular coils slightly anterior or posterior to the vertex will routinely activate corticofugal output from the medial parts of both hemispheres, including major inspiratory and expiratory muscles in normal subjects, and structures as lateral as the hand area are also activated. More focal stimulation can be achieved with double or "butterfly" coils. There are several nonstandard coils, but their properties must be carefully determined before their clinical utility can be assessed.

To obtain minimal latencies for response to transcranial stimulation, and thereby to avoid coming to the erroneous conclusion that there is a deficit in corticospinal conduction, it is best to record them during voluntary (or reflex) contractions producing at least 10% of maximal force. Responses can be obtained without a background contraction, but the latencies are more variable.

The presence of cardiac or other implanted electrical devices, including pacing wires and pulmonary artery catheters equipped with thermisters, is an absolute contraindication for magnetic stimulation and for high-voltage electrical stimulation of cranial or spinal structures. Epilepsy and known intracortical pathology are relative contraindications for cranial stimulation, as is the presence of intracranial clips.

Although transcranial stimulation has now been used for well over a decade with few reports of side effects, two issues deserve mention. First, there is a risk of induction of a seizure, particularly in those with pre-existing cortical pathology (such as a recent cerebrovascular accident). Although seizures have not been observed with repeated single stimuli, greater precautions are necessary for the newer rapid-rate stimulators (72, 73). Second, the use of some but not all transcranial magnetic stimulators has caused sustained elevations in auditory threshold, presumably due to the brief, but high-intensity "click" produced by the stimulus passing into the coil.

Data Analysis
Nerve stimulation is essential for measurements of nerve conduction velocity or latency. Furthermore, the electromyographic signal elicited by supramaximal nerve stimulation (CMAP) provides a different perspective than spontaneous EMG, with two distinct advantages: assurance of maximal activation, and a generally higher signal-to-noise ratio. CMAPs are detected, usually with surface electrodes applied over the costal margin, and the time between triggering of the stimulus and detection of the elicited CMAP is recorded. In most cases, CMAP amplitude and/or area are also recorded.

Latencies can also be measured after cortical stimulation (Figure 7) . The "central" conduction time (CCT) is an indirect estimate of the time taken for the descending volley to travel from the motor cortex to the relevant motoneurons. The CCT can be measured by subtraction of the peripheral conduction time (estimated by stimulation over the relevant spinal segment or root) from the total conduction time, from stimulus to onset of the motor-evoked potential (MEP). The measured CCT, however, is not a true measurement of central conduction velocities, because the exact site and timing of the relevant descending corticofugal volleys show some variability and because stimulation over the spinal cord activates the motor axons at a variable distance from the motoneurons. The MEP observed in EMG recordings of most human trunk and neck muscles, including diaphragm, intercostals, scalene, and abdominal muscles (64), has an onset latency consistent with a rapidly conducting oligosynaptic pathway. There is no evidence that this MEP involves a contribution from bulbopontine respiratory neurons.

View larger version (12K): [in this window] [in a new window]   Figure 7. Comparison of motor latencies and compound diaphragm or deltoid action potentials elicited by magnetic stimulation at the phrenic nerve, spinal level, and cortical level. The latencies are indicated in milliseconds. Bil. = bilateral; C4 = level of the 4th cervical root. Reprinted by permission from Reference 64.

During voluntary contraction, the minimal latency of responses is reduced, and the MEPs are increased in size compared with relaxation (Figure 8) , reflecting increased excitability not only at the spinal level (76) but also at the motor cortex (77). For the diaphragm, this effect has been documented during both volitional efforts (35) and CO₂-driven hyperpnea (78).

View larger version (19K): [in this window] [in a new window]   Figure 8. Effects of cortical stimulation at rest and during voluntary inspiratory efforts of varying strength. Left: Transdiaphragmatic pressure (Pdi) twitches obtained by bilateral supramaximal phrenic nerve stimulation during relaxation (thick trace). The thin traces show twitches resulting from transcranial magnetic stimulation (stimulator set at 85% maximal) at rest (lowest trace, no twitch) and during three graded static inspiratory efforts. Note the facilitation of Pdi twitches at intermediate voluntary efforts and the partial occlusion at high effort. Right: Compound muscle action potentials (CMAPs) recorded from surface electrodes on right and left chest wall (over the diaphragm) during magnetic stimulation at the four levels of voluntary effort shown at left. Note the progressive facilitation in CMAP amplitude. Reprinted by permission from Reference 76.

When cortical stimulation is delivered during voluntary effort, the MEP is followed by a period of near silence in the EMG recorded from the relevant muscle. The latter part of the silent period is due to inhibition of motor cortical output (79–81). The duration of the silent period grows with increasing intensity of cortical stimulation but does not vary greatly with the relative strength of voluntary contraction.

Applications
Normal phrenic nerve/diaphragm latencies, elicited by electrical stimulation at the neck, have been reported to average 6–8 milliseconds in adults (12, 16, 82, 83), with lower values in children (see Table 4). Because the right phrenic nerve is shorter than the left, latency is slightly shorter on the right side. CMAP amplitudes, recorded from chest wall surface electrodes, average 500–800 mV. Normal values for magnetic stimulation-induced phrenic nerve/diaphragm latency or for intercostal nerve/muscle latency have not been fully established (84, 85).

CCTs from cortex to phrenic motoneurons are approximately 4 milliseconds in normal adults (35). Normal values for D- and I-wave amplitudes and the effects of disease are not yet established, but it is apparent that I-wave amplitude is reduced by general anesthetic agents.

Transcranial stimulation to determine CCT has been used in the assessment of a range of upper motor neuron disorders and particularly in the assessment of patients with possible CNS demyelination, including multiple sclerosis. It can be applied specifically to the respiratory muscles, or, more commonly, to muscles in both upper and lower limbs.

Compound muscle action potentials (CMAP) in response to electrical or magnetic nerve or cortical stimulation can also provide useful information. Lack of a CMAP after nerve stimulation is an indication of paralysis, with the lesion located proximal to or at the neuromuscular junction. Lack of a CMAP in response to cortical stimulation when a CMAP is elicited by phrenic nerve stimulation has been used to identify good candidates for phrenic nerve pacing.

Changes in CMAP amplitude, especially as compared with changes in elicited muscle twitch strength (such as phrenic stimulation-induced diaphragm CMAP as compared with transdiaphragmatic twitch pressure [Pdi,tw]) can be used as evidence for or against the development of neural or neuromuscular transmission defects (when both Pdi,tw and CMAP decrease) or contractile defects (when Pdi,tw decreases but CMAP does not) (86).

CONCLUSION
In a manner analogous to the use of the electrocardiogram to assess cardiac function, electrophysiological tests of respiratory muscles—respiratory muscle motor latencies and electromyography—can be used to assess (1) respiratory drive, respiratory muscle coordination, and the level of activation of individual muscles; (2) the presence of neural and neuromuscular pathology; and (3) the apparent efficacy of the contractile function of the muscles, when used in conjunction with measurements of contractile force. The special challenges presented by data analysis complexity and by a host of potential artifacts lead to the need for great care in the application of EMG techniques to respiratory muscles. Nevertheless, neurophysiological tests are emerging as indispensable components of the respiratory muscle physiologist's arsenal.

SUMMARY
This Section of the Statement has described available electrophysiologic tests, the functions of which are to assess the integrity of the respiratory neuromotor apparatus. These electrophysiologic tests are technically complex and require considerable expertise.

There are two main types of test: electromyography (EMG) and stimulation tests.

Type 1: EMG.
For the respiratory muscles the EMG can be used to assess the level and pattern of activation, to detect and diagnose neuromuscular pathology, and when combined with tests of mechanical function to assess the efficacy of contraction.

The EMG can be recorded with surface electrodes (for diaphragm, intercostal, scalene, abdominal, and accessory muscles) or an esophageal electrode (for the crural diaphragm). Surface electrodes are noninvasive and sample a large number of motor units, but contamination (cross-talk) from other muscles is a substantial problem, as is the effect of body size and shape on signal amplitude. Esophageal electrodes provide more specific information, but the technique is invasive and complex.

Surface and esophageal electrodes can record the interference pattern EMG (raw EMG) of the respiratory muscles and are useful to determine the timing and level of respiratory muscle activation during breathing, at rest, and under load. Frequency domain analysis of the EMG is used, as a research tool, to investigate respiratory muscle fatigue (discussed in Section 5 of this Statement).

Intramuscular electrodes can be used to record, relatively selectively, from the diaphragm and intercostal muscles. Motor neuron firing frequency can be measured and neuromuscular disorders diagnosed. However, the techniques are invasive and technically difficult.

Type 2: Stimulation Tests.
Stimulation tests measure the efficiency of neural and neuromuscular transmission.

Nerve stimulation can be achieved with electrical or magnetic stimulators. Electrical stimulation is inexpensive and relatively selective, but is uncomfortable and can be technically difficult. Magnetic stimulation is easier to achieve and less uncomfortable, but can be less selective and is expensive.

Most commonly the phrenic nerves are stimulated and the diaphragm EMG elicited, for the measurement of phrenic nerve/diaphragm latencies and CMAP amplitudes. Latencies are prolonged in some neuromuscular disorders (e.g., demyelination) and CMAP is reduced in amplitude (e.g., traumatic damage to the phrenic nerves).

Cortical stimulation is most commonly performed with a magnetic stimulator, and permits the measurement of central conduction times (CCT) for limb muscles and diaphragm. CCT can be prolonged as, for example, in multiple sclerosis. Cortical stimulation is not selective, and the application of the technique to the respiratory system is a highly specialized skill.

	REFERENCES

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