Use of Sniff Nasal-Inspiratory Force to Predict Survival in

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					Use of Sniff Nasal-Inspiratory Force to Predict Survival
in Amyotrophic Lateral Sclerosis
Ross K. Morgan*, Stephen McNally*, Michael Alexander, Ronan Conroy, Orla Hardiman,
and Richard W. Costello

Departments of Medicine, Neurology, and Epidemiology, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland


Respiratory muscle weakness is the usual cause of death in amyotro-                   difficult to perform when the bulbar muscles are affected. The
phic lateral sclerosis. The prognostic value of the forced vital capac-               lack of a single test with a predictive value for mortality in ALS
ity (FVC), mouth-inspiratory force, and sniff nasal-inspiratory force                 has been emphasized in a prior evidence-based review (5).
were established in a group of 98 patients with amyotrophic lateral                      A sniff is a short, sharp, voluntary inspiratory maneuver.
sclerosis who were followed trimonthly for 3 years. Sniff nasal-                      Prior studies have shown that the maximal sniff nasal-inspiratory
inspiratory force correlated with the transdiaphragmatic pressure                     force (SNIF) correlates well with invasive and nonvolitional tests
(r 0.9, p 0.01). Sniff nasal-inspiratory force was most likely to
                                                                                      of diaphragm strength (6). Prior studies have identified that the
be recorded at the last visit (96% of cases), compared with either
                                                                                      SNIF is sensitive to changes in respiratory muscle strength (7).
the FVC or mouth-inspiratory force (86% and 81%, respectively,
                                                                                      Thus the SNIF test may be a good way to monitor respiratory
p     0.01). A sniff nasal-inspiratory force less than 40 cm H2O was
significantly related with nocturnal hypoxemia. When sniff nasal-                     muscle strength as the disease progresses. Furthermore, using
inspiratory force was less than 40 cm H2O, the hazard ratio for                       these data, it should be possible to establish a predictive relation-
death was 9.1 (p        0.001), and the median survival was 6       0.3               ship between SNIF and survival in patients with ALS. Hence,
months. The sensitivity of FVC 50% for predicting 6-month mortal-                     the hypothesis of this study was that SNIF values could be related
ity was 58% with a specificity of 96%, whereas sniff nasal-inspiratory                to the prognosis of ALS. To do this, we prospectively recorded
force less than 40 H2O had a sensitivity of 97% and a specificity of                  measures of respiratory muscle function over a 3-year period in
79% for death within 6 months. Thus the sniff nasal-inspiratory                       consecutive patients referred to a specialist ALS clinic. The
force test is a good measure of respiratory muscle strength in amyo-                  results of these studies have already been presented in abstract
trophic lateral sclerosis, it can be performed by patients with ad-                   form (8).
vanced disease, and it gives prognostic information.

Keywords: noninvasive ventilation; respiratory failure; respiratory
                                                                                      METHODS
muscle strength                                                                       Ninety-eight patients diagnosed with ALS by El Escorial criteria (9)
                                                                                      were studied trimonthly for 3 years at a specialist ALS clinic. The
Amyotrophic lateral sclerosis (ALS) is a common neurologic                            clinic is staffed by a neurologist, specialist nurse, speech and language
disease associated with an inexorable decline in muscle strength                      therapist, occupational therapist, dietician, and respiratory technician.
(1). Most patients with ALS die of respiratory failure resulting                      No patients declined to be enrolled and none were enrolled in other
from respiratory muscle weakness. A forced vital capacity (FVC)                       clinical trials of potentially disease-modifying drugs during the course
of less than 50% of the predicted value has been shown to be                          of this study. All patients were prescribed riluzole. No subject had
associated with a poor prognosis (2, 3). An FVC less than 50%                         received ventilatory support and none had experienced an adverse
has since been used as an important endpoint in many clinical                         respiratory event before entry into the study. Because poor attendance
trials and decision-making events for patients with ALS.                              by patients with incapacity from advanced disease may give a bias
                                                                                      toward more mobile subjects, regular review at this clinic was encour-
    However, there are several reasons why FVC is not an ideal
                                                                                      aged by a liaison nurse and follow-up phone conversations with family
test of respiratory muscle strength in ALS. The FVC may not
                                                                                      members. Noninvasive positive pressure ventilation was recommended
fall until there is profound muscle weakness, a consequence of                        for patients with respiratory failure (PaCO2      6.5 Kpa in the morning
the sigmoid relationship of the lung pressure–volume curves (4).                      or mean oxygen levels 90% overnight) or an FVC 50%. The cause
Second, patients with bulbar muscle weakness cannot make a                            and date of death were obtained by examination of the death certificate,
tight seal around the mouthpiece; therefore, recorded values                          and independent verification that the death was from respiratory failure
may not reflect the patient’s true respiratory muscle strength.                        was obtained from a community-based liaison nurse who visited the
Tests of respiratory muscle strength such as the maximal mouth-                       patients during the terminal phase of the illness. Subjects were divided
inspiratory force (MIF) and maximal mouth-expiratory force                            into bulbar- and nonbulbar-onset ALS. Bulbar-onset ALS referred to
are related to survival in ALS. However, these tests are also                         the population of patients who presented with upper and lower motor
                                                                                      neuron signs in the bulbar region as their first reported symptoms.
                                                                                      Verbal informed consent was obtained from all subjects. The hospital’s
                                                                                      ethics committee approved the study.

(Received in original form March 10, 2004; accepted in final form October 20, 2004)   Spirometry
Supported by financial assistance from the Motor Neuron Disease Association of        The same experienced qualified respiratory technician performed the
Ireland.                                                                              tests, and subjects were given adequate time to rest between the tests.
* These authors contributed equally to this manuscript.                               At each visit, the FVC was recorded with a Microlab spirometer (Micro-
                                                                                      Medical Limited, Rochester, Kent, UK) using standards recommended
Correspondence and requests for reprints should be addressed to Richard W.
Costello, Department of Medicine, Royal College of Surgeons in Ireland, Beaumont
                                                                                      by the American Thoracic Society. The best of three reproducible
Hospital, Dublin 9, Ireland. E-mail: rcostello@rcsi.ie                                values was recorded. Where necessary, the maximal arm span was used
                                                                                      to establish a percent predicted value.
This article has an online supplement, which is accessible from this issue’s table
of contents at www.atsjournals.org
                                                                                      Recording MIF and Maximal Expiratory Force
Am J Respir Crit Care Med Vol 171. pp 269–274, 2005
Originally Published in Press as DOI: 10.1164/rccm.200403-314OC on October 29, 2004   MIF and maximal expiratory force (MEF) were measured using a hand-
Internet address: www.atsjournals.org                                                 held pressure meter with a flanged mouthpiece (MicroMedical Limited).
270                                                      AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 171 2005

The subject was instructed to suck in/blow out as hard as possible and       TABLE 1. SUBJECT CHARACTERISTICS AND LUNG FUNCTION
the best of six tests of at least 1-second duration were recorded.           ENTRY INTO THE STUDY (MEAN      SD UNLESS
                                                                             OTHERWISE INDICATED)
Recording Nasal Inspiratory and Expiratory Force
                                                                             Onset                                  Bulbar                    Nonbulbar
At the start of this study, a commercial nasal inspiratory pressure
meter was not available, so the device used for MIF measurements was         Subjects (n 98)                         30                          68
modified for SNIF measurements. A plug was inserted into a nostril            Age, yr                            60.57 10.44                 58.94 12.12
and the center of this plug snugly held the tip of a polyethylene catheter     Range                                40–85                       23–83
(Intersurgical Scientific Instruments, Oxford, UK) within the nasal cav-      Sex, M/F                               14/16                       44/24
                                                                             BMI, kg/m2                          25.4 5.2                    24.1 3.2
ity. This polyethylene catheter was 30 cm in length and had an internal
                                                                               Range
diameter of 2 mm and the other end was attached to the hand-held
                                                                             Duration of disease, mo              8.4 10.5                   13.2 16
pressure transducer (a photomicrograph of the device is shown in Figure
                                                                               Range                                 3–45                        3–79
E1 in the online supplement). The contralateral nose was occluded and        FVC, % predicted                    70.7 24.7                   81.8 25.4
the patients were instructed to close the mouth and to breathe out and       MIF, cm H2O                         37.9 16.3                   52.4 33.5
then to take a deep sniff or a maximal inspiratory effort from end-          MEF, cm H2O                         43.9 22.0                   67.3 43.6
expiratory lung volume or to breathe in and then to make an expiratory       SNIF, cm H2O                        43.6 24.7                   53.8 25.6
effort from end-inspiratory lung volume. Because a subject’s nasal pas-      SNEF, cm H2O                        64.4 43.7                   75.1 39.8
sages may be blocked, recordings were taken from both nostrils (left
side first) and the highest of six recorded values sustained for over           Definition of abbreviations: BMI body mass index; MEF    maximal expiratory
1 second was recorded. An initial validation study was performed in          mouth force; MIF maximal inspiratory mouth force; SNEF    sniff nasal-expiratory
102 healthy control subjects (age range 20–86; mean age 46.3 years).         force; SNIF sniff nasal-inspiratory force.

Recording Oxygen Levels During Sleep
A domiciliary watch oximetry (Minolta Pulsox-3 Oxygen situation mon-
itor, Stowood Scientific Instruments, Oxford, UK) was used to record          required a wheelchair for mobility at the point of first recording
oxygen saturations. The device recorded oxygen saturation levels at          of respiratory muscle strength. At the time of entry into the
4-second intervals. The device’s computer software (Minolta Pulsox,
                                                                             study, the mean FVC was 78         25%, and the SNIF and MIF
version 3.02, Stowood Scientific Instruments) was used to remove obvi-
ous errors from device displacement and to obtain the mean oxygen            were also diminished at 51.6      21.7 and 47.3     22.4 cm H2O.
saturations and the proportion of recording time spent with oxygen           Over the study period, there were 271 visits, and 71 patients had
saturation less than 90%.                                                    more than two recordings performed. Measures of respiratory
                                                                             muscle strength were obtained in 87% of subjects within 3
Transdiaphragmatic Pressure                                                  months of death and were obtained in 97% within 6 months of
Esophageal pressures (Pes) and gastric pressure (Pgas) were recorded         death. During the course of the study, 20 subjects were started on
using a Grass polygraph (Grass Telefactor; Astro-Med, Inc., West War-        noninvasive ventilation, but no subject was placed on mechanical
wick, RI); transdiaphragmatic pressure (Pdi) was calculated in a subgroup    ventilation. Of these, eight tolerated the device and used it at
of 24 subjects. After calibration, a silastic tube with two separate air-
                                                                             home. The mean survival for this group was 4.2 4.3 months,
filled pressure probes was inserted into one nostril. The subjects were
instructed to swallow and the tube was passed through the oropharynx         and 2.2 1.4 months for the group who did not use the device.
with each swallow. Direct visualization of the pressure tracing produced
with each sniff was used to position the tube so that one probe recorded     SNIF Correlates Well with Invasive Measurement
gastric pressure (positive deflection during inspiration) and the other       of Respiratory Muscle Strength
recorded esophageal pressure (negative deflection during inspiration).
                                                                             An initial validation study was performed in 102 healthy control
Subjects were then instructed to sniff, and measures of esophageal
pressure and transdiaphragmatic pressure were recorded (gastric pres-        subjects (age range 20–86, mean age 46.3 years). The mean SNIF
sure, esophageal pressure).                                                  was 90      31 cm H2O; for SNEF, it was 134        48 cm H2O.
                                                                             Transdiaphragmatic pressure was assessed in a subgroup of 24
Statistical Analysis                                                         subjects, 12 of whom had bulbar disease. A good concordance
Statistical analysis was performed using StataSE release 8.1. Data were      of SNIF to transdiaphragmatic pressure was seen (rho_c 0.661)
expressed as event history data, which allows participants to be switched    (Figure 1 and Table 2).
between at-risk groups on the basis of their most recently measured
clinical parameters. Where clinical measurements could not be made
at a particular follow-up, values were carried forward until the next
measurement. Analysis was by most recent value of clinical parameters.
Cox regression was used to model the prognostic effect of the clinical
parameters studied. To examine the relationship between different
noninvasive measurements of respiratory muscle strength and transdia-
phragmatic pressure were calculated using Lin’s concordance coefficient
(10, 11). This is a measure of agreement that is scaled between zero and
one. To overcome differences of scale, all measures were transformed by
ranking them. The concordance coefficient therefore represents the
agreement in rank order between each of the measures and transdia-
phragmatic pressure. Kaplan-Meier survival was calculated and used
to identify survival quantiles.

RESULTS
The demographic details of the subjects, at the time of entry                Figure 1. There is a strong correlation between sniff nasal-inspiratory
into the study are given in Table 1. Ninety-eight patients were              force (SNIF) and transdiaphragmatic pressure (Pdi). Graph shows SNIF
studied, and over the 3 years, 39 of these died. The mean duration           versus Pdi in 22 subjects. Solid triangles represent bulbar subjects. R2
of symptoms before enrollment was 11.7 months, and 13 patients               0.6445; p     0.0001.
Morgan, McNally, Alexander, et al.: Nasal Sniff Test in ALS                                                                                  271

SNIF is a Reproducible Test in Advanced ALS                                 O2 and proportion of night spent at less than 90% O2 saturation
The ability of each of the 98 subjects to perform a reproducible            were related to death.
test of each of the measures of respiratory strength at their last             A SNIF less than 40 cm H2O was associated with a hazard
visit before death or study completion is shown in Figure 2. The            risk for death of 9.1 (95% CI 4–20.8, p        0.001) (Figure E2).
SNIF was significantly more likely to be recorded than either                The 25th percentile for mortality when the SNIF fell to less than
the FVC or MIF (p 0.01; Figure 2). Among all subjects, only                 40 cm H2O was 3.46 0.1 months (95% CI 2.51–5.52) and the
four (4%) were unable to record a SNIF; two of these subjects               median (50%) mortality was 6 0.3 months (95% CI 2.51–8.45).
had severe bulbar weakness: one had a deviated nasal septum                 When the eight patients who used noninvasive ventilation were
and one subject’s anterior nares was too large to retain the nasal          excluded from the data set, there was still no effect on the major
plug during the maneuver. Fourteen subjects (14%), all with                 result of the study (i.e., that SNIF 40 cm H2O was a positive
significant bulbar dysfunction, were unable to perform a repro-              predictor of death; data not shown). Figure 5 shows the Kaplan-
ducible FVC recording. MIF could not be obtained in 19 (19%)                Meier survival curve for all subjects separated into change of
subjects, all of whom had bulbar weakness. These subjects all               SNIF of 10 cm H2O. The hazard ratio for death when the SNIF
reported difficulty in performing the test against a closed airway,          was less than 30 cm H2O compared with those with a SNIF more
a commonly identified problem with the MIF test, even in indi-               than 30 cm H2O was 5.9 (95% CI 3–12). When FVC fell to less
viduals with normal muscle function (4, 12).                                than 50%, the hazard ratio for death was 5.66 (95% CI 2.73–
                                                                            11.73, p 0.001).
Relationship Between Overnight Oximetry and FVC, MIF,                          Among patients with a SNIF less than 40 cm H2O, 66% had
and SNIF                                                                    an FVC greater than 50%; in this group, the hazard ratio for
Fifty-seven subjects had overnight oximetry performed, although             death was 13.6 (95% CI 3.1–54.7, p          0.001) (Table 3). We
not all of these subjects could perform all of the measures of              defined sensitivity as the proportion of subjects who died when
respiratory muscle strength. Correlation analysis of the mean               their measurements were FVC less than 50% and MIF and SNIF
nocturnal oxygen saturation levels to SNIF was r       0.4, p
0.001; for MIF, r     0.322, p   0.056; and for FVC, r      0.39,
p 0.003 (Figure 3).

Threshold Levels of FVC, MIF, and SNIF to Predict Nocturnal
Hypoxemia and Death
To evaluate the clinical relevance of the noninvasive tests for
predicting mortality, we used threshold levels for each test. The
association between FVC, MIF, and SNIF categories with time
spent at less than 90% oxygen saturation at night are shown in
Figure 4. Only SNIF category (above or below 40 cm H2O) was
significantly associated with desaturation on this analysis (p
0.01).

Predictors of Mortality in ALS
Each test was considered as a continuous variable, and Cox
regression analysis was used to examine the hazard ratios for
predicting death. Table E1 (in the online supplement) shows
the results of this analysis. Age, body mass index, FVC (%
predicted), SNIF, MIF, and SNEF were all independently associ-
ated with a significantly increased risk of death at any point of
follow-up. In addition, the oximetry variables measured; mean




Figure 2. SNIF measurement is possible even in severe disease and in
patients with bulbar disease. Graph shows the reproducibility of the        Figure 3. Reduced mean oxygen saturation during sleep is associated
noninvasive tests of respiratory muscle strength in patients with amyo-     with reductions in inspiratory pressures but not FVC. Graphs show the
trophic lateral sclerosis. Data represent the patients ability to perform   relationship between (top) SNIF (n     55), (middle) MIF (n 41), and
the measurement on their last study visit. R         reproducible; u/o      (bottom) FVC (n 51) in the same 55 patients, and the mean oxygen
unobtainable. Filled bars     bulbar; open bars    limb.                    saturation on overnight oximetry. Dashed line is drawn at 92%.
272                                                   AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 171 2005




                                                                          Figure 5. Kaplan-Meier survival curves based on the SNIF categories
                                                                             50 cm H2O,      50 cm H2O,     40 cm H2O, and    30 cm H2O. The
                                                                          hazard ratio for death for each change in 10 cm H2O was 0.6 (95% CI
                                                                          0.4–0.7, p    0.05).




                                                                          important prognostic factors in survival (2, 3, 13, 14). These
                                                                          studies have generally used the FVC as the main measure of
                                                                          respiratory muscle strength. The FVC is not a particularly good
                                                                          measure of respiratory muscle strength because the shape of the
                                                                          pressure–volume curve means that it does not detect modest
                                                                          falls in muscle strength. Thus alternative measures of muscle
                                                                          strength with MIF and SNIF testing have been investigated in
                                                                          some prior studies. One retrospective study demonstrated an
                                                                          association between MIF and survival, but did not establish a
                                                                          value that gave a guide to prognosis (15). Prior prospective
                                                                          studies have reported that composite respiratory scores—a com-
                                                                          bination of FVC and MIF—were related to survival. However,
                                                                          in these studies too, a threshold value for either test which
                                                                          provided prognostic information was not established (3, 14).
                                                                              The study population was prospectively recruited and fol-
                                                                          lowed over 3 years. Approximately 40% of the study subjects
                                                                          were women, reflecting the expected male:female ratio of 1.6:1
Figure 4. Scatterplots of the proportion of the night spent with an
oxygen saturation 90% on overnight oximetry compared with pulmo-
                                                                          in an ALS population. Although the average FVC was slightly
nary function tests are shown. Patients with an SNIF value of less than   reduced at the start of the study, the direct measures of muscle
40 cm H2O were significantly more likely to desaturate at night. Lines    strength, MIF and SNIF, were considerably reduced in most
represent mean for each group, *p      0.05%; NS     not significant.     patients. At the start of this study, a device to measure SNIF
                                                                          was not commercially available, so we modified a hand-held
                                                                          mouth pressure meter to record these pressures. To establish the
                                                                          reliability of this new device, we undertook a series of validation
                                                                          studies, testing the fidelity of the recording device and establish-
less than 40 cm H2O 6 months before death and the specificity              ing a range of values of SNIF in a cohort of healthy volunteers
as the proportion of subjects who lived for more than 6 months            of a similar age as the ALS patients. The mean value of SNIF
when their test was above the cutoff value. The sensitivity of
FVC less than 50% for predicting 6-month mortality was 58%
with a specificity of 96%, whereas for SNIF less than 40 cm H2O,
the test had a sensitivity of 97% and a specificity of 79% for             TABLE 2. RELATIONSHIP BETWEEN TESTS OF RESPIRATORY
                                                                          MUSCLE STRENGTH AND TRANSDIAPHRAGMATIC
death within 6 months (Table 4).
                                                                          PRESSURE AND CONCORDANCE BETWEEN
                                                                          TRANSDIAPHRAGMATIC PRESSURE AND
DISCUSSION                                                                TESTS OF MUSCLE STRENGTH
The results of this study show that SNIF correlated well with                                  n (%)          rho_c           95% CI             p Value
transdiaphragmatic strength and so is a good measure of respira-
                                                                          Pes                24   (100)       0.844        0.727–0.962             0.001
tory muscle strength. Furthermore, at the later stages of the             SNIFmax            22   (91)        0.661        0.410–0.906             0.001
disease, the SNIF test could still be performed by 96% of the             FVC %pred          19   (79)        0.643        0.403–0.883             0.001
patients. Finally, we established that a SNIF less than 40 cm             MIFmax             18   (75)        0.466        0.119–0.814             0.009
H2O is associated with a median survival of 6 months. Thus the            MEF                18   (75)        0.372        0.025–0.769             NS
SNIF test is a sensitive means of detecting respiratory muscle            SNEF               22   (91)        0.252        0.022–0.527             NS
strength, it can be recorded in advanced disease, and it gives              Definition of abbreviations: MEF    maximal expiratory mouth force; MIF
important prognostic information.                                         maximal inspiratory mouth force; NS nonsignificant; Pes esophageal/pleural
   Prior studies of the natural history of ALS have identified             pressure; rho_c    Lin’s concordance coefficient; SNEF   sniff nasal-expiratory
that deteriorations in pulmonary function tests are the most              force; SNIF sniff nasal-inspiratory force.
Morgan, McNally, Alexander, et al.: Nasal Sniff Test in ALS                                                                                                        273

TABLE 3. INCREASED RISK OF DEATH FROM RESPIRATORY                                   tion. Studies in our unit are in progress to establish if initiation
FAILURE IN PATIENTS WITH AN FVC ( 50% PREDICTED)                                    of nocturnal ventilatory support leads to increased survival when
WHOSE SNIF HAS FALLEN BELOW 40 cm H2O (PROPORTION
WITH FVC GREATER THAN 50% PREDICTED IN EACH SNIF
                                                                                    the SNIF falls to this level.
GROUP AND HAZARD RATIO OF DEATH IN 6 MONTHS)                                            Noninvasive ventilation may prolong life and improve quality
                                                                                    of life in patients with ALS (17–19). However, there is no consen-
                   Proportion with                                                  sus on when to initiate this treatment (20). The timing of institut-
SNIF Category        FVC 50%            Hazard Ratio         95% CI       p Value
                                                                                    ing ventilatory support and discussion of the overall prognosis
  60 cm H2O               98%                 —                —            —       are important issues for patients. The prognosis, the recom-
40–59 cm H2O              90%                 3.88        0.613–24.6        0.149   mended timing of noninvasive ventilation, and assessment of
  40 cm H2O               66%                13.6          3.08–54.69       0.001   new treatments in ALS all use FVC% as the standard measure
  Definition of abbreviation: SNIF    sniff nasal-inspiratory force.
                                                                                    of respiratory performance (21, 22). The results of this study
  p 0.05 is significant.                                                            highlight the limitations of using the FVC in ALS. First, it cannot
                                                                                    be obtained in about 20% of subjects at the later stages of the
                                                                                    disease, and second, it is not sensitive to important changes
                                                                                    in respiratory muscle strength because 75% of subjects with
was 90 cm H2O, which is in agreement with prior data, suggesting                    important levels of muscle weakness (SNIF          40 cmH2O) still
that our modified device was suitable for this study (16). In                        had an FVC greater than 50%. This is important because, in
addition, we related SNIF, MIF, and FVC to transdiaphragmatic                       this group, the hazard ratio for death within 6 months was 13.6.
muscle strength in a subgroup of patients with ALS. In these                        In summary, the SNIF is a valuable tool to monitor respiratory
studies, it was shown that both MIF and SNIF correlated better                      muscle strength in patients with ALS.
with transdiaphragmatic pressure than with FVC. This confirms                        Conflict of Interest Statement : R.K.M. does not have a financial relationship with
the results of prior studies indicating that MIF and SNIF are                       a commercial entity that has an interest in the subject of this manuscript; S.M.
better methods of recording respiratory muscle strength than                        does not have a financial relationship with a commercial entity that has an interest
                                                                                    in the subject of this manuscript; M.A. does not have a financial relationship with
FVC. We had noticed, clinically, that weakness of the bulbar                        a commercial entity that has an interest in the subject of this manuscript; R.C.
muscle often prevents patients from making a complete seal                          does not have a financial relationship with a commercial entity that has an interest
around a mouth device; consequently, FVC and MIF may not                            in the subject of this manuscript; O.H. does not have a financial relationship with
                                                                                    a commercial entity that has an interest in the subject of this manuscript; R.W.C.
be recorded accurately at a time when the information is most                       does not have a financial relationship with a commercial entity that has an interest
relevant. In the current study, 4 patients (4%) could not perform                   in the subject of this manuscript.
SNIF at the last visit, whereas 14 (14%) and 19 (19%) could
                                                                                    Acknowledgment : The authors are grateful to the patients who participated in
not perform the FVC and MIF, respectively. Thus, although
                                                                                    this study.
MIF and SNIF are better tests of respiratory muscle strength
than FVC, more patients with advanced disease can perform the
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