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: email@example.com 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. 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