J Neurol (2015) 262:593–603 DOI 10.1007/s00415-014-7613-3

ORIGINAL COMMUNICATION

Sniff nasal inspiratory pressure as a prognostic factor of tracheostomy or death in amyotrophic lateral sclerosis Rosa Capozzo • Vitaliano N. Quaranta • Fabio Pellegrini • Andrea Fontana • Massimiliano Copetti • Pierluigi Carratu` • Francesco Panza • Anna Cassano • Vito A. Falcone • Rosanna Tortelli • Rosa Cortese • Isabella L. Simone • Onofrio Resta • Giancarlo Logroscino

Received: 26 September 2014 / Revised: 4 December 2014 / Accepted: 6 December 2014 / Published online: 19 December 2014 Ó Springer-Verlag Berlin Heidelberg 2014

Abstract Forced vital capacity (FVC) shows limitations in detecting respiratory failure in the early phase of amyotrophic lateral sclerosis (ALS). In fact, mild-tomoderate respiratory muscle weakness may be present even when FVC is normal, and ALS patients with bulbar involvement might not be able to perform correctly the spirometry test. Sniff nasal inspiratory pressure (SNIP) is correlated with transdiaphragmatic strength. We evaluated SNIP at baseline as a prognostic factor of tracheostomy or death in patients with ALS. In a multidisciplinary tertiary care center for motorneuron disease, we enrolled 100 Electronic supplementary material The online version of this article (doi:10.1007/s00415-014-7613-3) contains supplementary material, which is available to authorized users. R. Capozzo  F. Panza  R. Tortelli  R. Cortese  I. L. Simone  G. Logroscino (&) Neuroscience and Sense Organs, Department of Basic Medical Science, Neurodegenerative Diseases Unit, University of Bari ‘‘Aldo Moro’’, Bari, Italy e-mail: [email protected] V. N. Quaranta  P. Carratu`  A. Cassano  V. A. Falcone  O. Resta Pulmonary Disease Institute, University of Bari ‘‘Aldo Moro’’, Bari, Italy F. Pellegrini  A. Fontana  M. Copetti Unit of Biostatistics, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, FG, Italy F. Pellegrini Unit of Biostatistics, Consorzio Mario Negri Sud, Santa Maria Imbaro, CH, Italy F. Panza  R. Tortelli  G. Logroscino Department of Clinical Research in Neurology, University of Bari ‘‘Aldo Moro’’, ‘‘Pia Fondazione Cardinale G. Panico’’, Tricase, LE, Italy

patients with ALS diagnosed with El Escorial criteria in the period between January 2006 and December 2010. Main outcome measures were tracheostomy or death. RECursive Partitioning and AMalgamation (RECPAM) analysis was also used to identify subgroups at different risks for the tracheostomy or death. Twenty-nine patients with ALS reached the outcome (12 died and 17 had tracheostomy). Using a multivariate model SNIP correctly classified the risk of the composite event within 1 year of follow-up with a continuous Net Reclassification Improvement cNRI of 0.58 (p = 0.03). Sex, Amyotrophic Lateral Sclerosis Functional Rating Scale revisited, site of onset, and FVC did not improve the classification of prognostic classes. SNIP B18 cmH2O identified the RECPAM class with the highest risk (Class 1, hazard ratio = 9.85, 95 % confidence interval: 2.67–36.29, p \ 0.001). SNIP measured at baseline identified patients with ALS with initial respiratory failure. Finally, using only ALS patients with spinal onset of the disease, our findings were mostly overlapping with those reported in the models including the whole sample. At baseline, SNIP appeared to be the best predictor of death or tracheostomy within 1 year of follow-up. The measurement of SNIP in the early phase of the disease may contribute to identify patients with high risk of mortality or intubation. SNIP may also provide an additional tool for baseline stratification of patients with ALS in clinical trials. Keywords SNIP  FVC  Prognosis  Respiratory function  ALS Abbreviations ALS Amyotrophic lateral sclerosis ALSFRS-R Revised amyotrophic lateral sclerosis Functional Rating Scale

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AUC BDI EI FAB FVC FTD NIV MMSE MMT MoCA 95 % CI RECPAM ROC SD SDMT ST VFT

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Area under the receiver operating characteristic Curve Beck Depression Inventory Executive index Frontal Assessment Battery Forced vital capacity Frontotemporal dementia Noninvasive ventilation Mini-Mental State Examination Manual muscle testing Montreal Cognitive Assessment 95 % confidence intervals RECursive Partitioning and Amalgamation Receiver-operating characteristic Standard deviation Symbol Digit Modalities Test-Oral version Stroop test Verbal Fluency Test

Introduction Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder involving motorneurons. Most ALS deaths are due to the impairment of pulmonary functions resulting from respiratory muscles weakness [1]. Management of respiratory failure is based on non-invasive ventilation (NIV) or tracheostomy with fully informed consent may be offered when NIV is no longer effective [2]. Some patients with ALS require early respiratory support, while others may have a relatively prolonged survival [3]. Nonrespiratory factors including female gender, advanced age, short interval symptoms onset-to-diagnosis, bulbar onset, altered nutritional status, and low score of Amyotrophic Lateral Sclerosis Functional Rating Scale revisited (ALSFRSr) are associated with shorter survival [4]. Forced vital capacity (FVC) is an index of respiratory failure commonly used to evaluate the respiratory dysfunction in patients with ALS [5]. FVC B50 % of the standardized predicted value has been correlated to a poor prognosis [6]. FVC is important for clinical planning and stratification in clinical trials of patients with ALS [7, 8], but it may not be an ideal test to diagnose respiratory dysfunctions in the early phase of ALS. In fact, given the sigmoid relationship of the lung pressure–volume curve [9], FVC may not fall until the development of a severe muscle weakness. Mild-to-moderate respiratory muscle weakness may be present even when FVC is normal [10]. Furthermore, patients with bulbar involvement might not be able to perform correctly the spirometry test [11], requiring the full activation of respiratory muscles.

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Sniff nasal inspiratory pressure (SNIP), described in 1985 as an alternative test to assess respiratory functions [12], is a noninvasive maneuver which consists of measuring nasal pressure through a plug occluding one nostril during a maximal sniff performed through the contralateral nostril, from current volume. SNIP correlates with transdiaphragmatic strength and is sensible to small changes in respiratory functions [13, 14]. SNIP may give information about survival in patients with ALS [15, 16]. The aim of this study was to estimate the prognostic value of SNIP measured at baseline in a cohort of patients with ALS within 1 year of follow-up.

Methods The present study was conducted according to the World Medical Association’s 2008 Declaration of Helsinki and the guidelines for Good Clinical Practice and the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) [17]. In this retrospective cohort study, we enrolled 100 patients with ALS referred to the multidisciplinary center for motorneuron disease at the University of Bari ‘‘Aldo Moro’’ in the period January 2006–December 2010. All ALS patients were diagnosed according to El Escorial criteria [18]. At baseline, the following variables were measured: sex, age, body mass index (BMI, kg/m2), date of onset of first symptom, date of diagnosis, ALSFRSr [19], FVC, SNIP, arterial partial pressure of oxygen, carbon dioxide, and Charlson Comorbidity Index (CCI) [20]. Patients were classified in bulbar or spinal-onset, referring to the presence of motor neuron signs in bulbar or spinal regions as their first reported symptoms. The outcomes were tracheostomy or death. Patients who neither underwent tracheostomy nor died, were considered censored assuming January 31st, 2011 as date of the final outcome. Our study protocol was approved by Local Ethical Committee and written informed consent was obtained from all patients. Respiratory tests were performed by experienced technicians under the supervision of a pneumologist. Spirometry was performed by a qualified respiratory technician (Spirometer PK Morgan Ldt; Gillingham, UK). The equipment was calibrated using a 3-L syringe and the analysis was performed according to the American Thoracic Society (ATS)/European Respiratory Society (ERS) Guidelines [21]. The FVC value was measured in sitting position. The best of three reproducible values, expressed as a percentage of the predictive normal value, was taken into account. To overcome air leakage from the mouth, a full-face mask was adapted for bulbar ALS patients. The sniff test (performed with the MicroRPM-Respiratory Pressure Meter) was used to assess the SNIP value in

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sitting position. SNIP is measured in one nostril during a maximal sniff performed through the contralateral nostril closed by a sealing plug. Patients were asked to breathe normally with a closed mouth and to perform at least five maximal sniffs, each separated by 30 s. The highest of recorded values sustained for over 1 s was recorded. The following criteria were used to select a suitable sniff: (a) a pressure curve showing a regular upstroke and a sharp peak and (b) a total sniff duration of less than 0.5 s [22] The plug-catheter was inserted in one nostril and the other extremity of the catheter was connected to a pressure transducter. The pressure was expressed in cmH2O. The patients were instructed to take a series of short sniffs with the mouth closed; the highest of five results was recorded. Statistical analysis Patients baseline characteristics were reported as frequency (percentages) and mean ± standard deviation (SD), or median and range, and comparisons between patients groups were performed using Pearson Chi-square and twosample t test (or Mann–Whitney U test as appropriated), for categorical and continuous variables, respectively. To test the presence of a linear trend across ordinal variables, Mantel–Haenszel Chi-square test was performed. Incidence rates for events (i.e., tracheostomy/death) were reported for 100 person-years. Pearson’s correlation coefficients were estimated to assess associations between continuous variables. Time-to-event analysis was performed with univariate and multivariate Cox proportional hazards regression models and risks were reported as hazard ratios (HR) along with their 95 % confidence interval (95 % CI). Time variable was defined as the time between the date of the first visit (baseline) and tracheostomy/death (whichever occurred first). Disease duration was defined as the time between disease onset and the date of the first visit. For subjects who did not experience any event, time variable was defined as the time between the baseline and the date of the last available clinical followup. The assumption of proportionality of the hazards was tested by using scaled Schoenfeld residuals. Two multivariate models were estimated. The first one was a clinical-based model which included: age, sex, BMI, CCI, ALSFRSr, FVC, site of onset, disease duration (‘‘Base’’ model). The second model included the SNIP variable as new predictor (‘‘Base plus SNIP’’ model). HR estimates for disease duration were reported for each unitary increase of 5 years. Improvements in model’s discriminatory power and risk reclassification provided by SNIP, within 1 year of follow-up, were assessed by modified c-statistic for censored survival data and the survivalbased continuous Net Reclassification Improvement (cNRI) [23], respectively, using predicted probabilities

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from multivariate Cox regressions. Furthermore, a sensitivity analysis to evaluate the net risk reclassification within a time horizon of 1, 1.5, 2, 2.5, and 3 years with different arbitrarily small positive quantities (epsilon) of differences in models’ risk probabilities was performed. Models’ calibration was assessed using the survivalbased Hosmer–Lemeshow goodness-of-fit test. Moreover, the receiver operating characteristic (ROC) curve analysis was used to detect the optimal cut-off both for SNIP and FVC, which jointly maximize the sensitivity and the specificity to detect events within 1 year of follow-up, also providing the area under the ROC curve (AUC). Finally, interactions between patients’ characteristics on the prediction of events risk were investigated using RECursive Partitioning and AMalgamation (RECPAM) algorithm, along with an internal validation of splits using a permutation approach. Sex, ALSFRSr, site of onset, FVC, and SNIP were included as candidate splitting variables, whereas age, CCI, and disease duration were used as global adjustment variables. Adjusted survival curves obtained from the RECPAM model were also reported. Finally, both univariate and multivariate Cox models using only spinalonset ALS patients have been performed. A p value \0.05 was considered statistically significant. All statistical analyses were performed using SAS Release 9.3 (SAS Institute, Cary, NC, USA).

Results Overall 29 of 100 patients (143 person-years, incidence rate: 20.25 %) died or had tracheostomy (12 deaths, 17 tracheostomy). The median follow-up time was 1.20 years (range 0.02–3.89 years). When patients were censored within 1 year of follow-up, the incidence of the composite event was 12 out of 85 person-years (cumulative incidence 14.07 %). Patients baseline characteristics also divided by the composite event status are reported in Table 1. In the whole sample, SNIP median value was 43.5 cmH2O (7.0–119.0), FVC median value was 81.6 % (20.3–131.0); mean age was 62.08 ± 10 years, 55 % were male, mean disease duration was 1.75 ± 1.63 years, 69 % of patients had spinal onset. SNIP was positively correlated to FVC (r = 0.47, p \ 0.001). Patients who experienced tracheostomy or death presented significant differences in SNIP (p \ 0.001) and FVC values at baseline (p = 0.023) compared to patients who did not reach the outcomes. Results from univariate Cox regression are reported in Table 2. Only SNIP (HR 0.98, 95 % CI 0.96–0.99, p = 0.005), FVC (HR 0.99, 95 % CI 0.97–1.00, p = 0.043), and ALSFRSr (HR 0.95, 95 % CI 0.91–0.99, p = 0.026) resulted significantly associated with the composite event.

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596 Table 1 Baseline characteristics of patients with amyotrophic lateral sclerosis divided by the composite event status

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Variable

Sex (n, %) BMI (kg/m2)

ALSFRSr

Charlson Comorbidity Index

Site of onset (n, %) Disease duration, from the onset to the first assessment (years)

* p values from two-sample t test and Chi-squared test for continuous and categorical variables, respectively ^ p value from Mann–Whitney U test #

p values from two-sample t test using log-transformed values

All subjects

100

29

71

Mean ± SD

62.08 ± 10.00

64.20 ± 8.09

61.25 ± 10.59

Median (min– max)

62.69 (36.59–81.30)

64.44 (46.60–78.27)

61.40 (36.59–81.30)

No. of patients Age (years)

BMI body mass index, ALSFRSr Amyotrophic Lateral Sclerosis Functional Rating Scale revisited, SNIP sniff nasal inspiratory pressure, FVC forced vital capacity

Category

SNIP (cmH2O)

FVC (%)

Follow-up (years)

Non-events

Females

45 (45.00 %)

14 (48.28 %)

31 (43.66 %)

Males

55 (55.00 %)

15 (51.72 %)

40 (56.34 %)

Mean ± SD

25.45 ± 3.99

25.15 ± 4.48

25.58 ± 3.80

Median (min– max)

25.28 (16.85–40.90)

24.22 (17.30–35.36)

25.39 (16.8540.90)

Mean ± SD

36.76 ± 7.23

34.83 ± 9.58

37.55 ± 5.92

Median (min– max)

38.00 (10.00–48.00)

38.00 (10.00–48.00)

38.00 (20.0048.00)

Mean ± SD

1.25 ± 1.11

1.14 ± 1.19

1.30 ± 1.09

Median (min– max)

1.00 (0.00–4.00)

1.00 (0.00–4.00)

1.00 (0.00–4.00)

Bulbar

31 (31.00 %)

12 (41.38 %)

19 (26.76 %)

Spinal

69 (69.00 %)

17 (58.62 %)

52 (73.24 %)

Mean ± SD

1.75 ± 1.63

1.34 ± 0.75

1.92 ± 1.85

Median (min– max)

1.41 (0.01–13.53)

1.36 (0.14–3.12)

1.42 (0.01–13.53)

B1.4 years (median)

49 (49.00 %)

15 (51.72 %)

34 (47.89 %)

[1.4 years (median)

51 (51.00 %)

14 (48.28 %)

37 (52.11 %)

Mean ± SD

47.78 ± 25.75

32.97 ± 20.95

53.83 ± 25.18

Median (min– max)

43.50 (7.00–119.00)

32.00 (7.00–96.00)

51.00 (14.00–119.00)

Mean ± SD

78.37 ± 25.45

69.34 ± 23.67

82.06 ± 25.39

Median (min– max)

81.60 (20.30–131.00)

72.80 (27.00–122.20)

83.00 (20.30–131.00)

Mean ± SD

1.43 ± 0.91

1.17 ± 0.66

1.54 ± 0.98

Median (min– max)

1.20 (0.02–3.86)

1.20 (0.02–2.68)

1.20 (0.38–3.86)

Although not statistically significant, subjects with spinal onset of disease had a decreased risk of the composite event (HR 0.56, 95 % CI 0.27–1.18, p = 0.128). Furthermore, the SNIP variable was categorized into units of 10 cmH2O below 70 cmH2O as following and related to the composite event: (1) C70; (2) between 50 and 70 (excluded); (3) between 40 and 50 (excluded); (4) between 30 and 40 (excluded); (5)\30. A univariate Cox regression was performed to assess the statistical association of this

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Events (tracheostomized/ death patients)

p value*

0.187

0.674 0.627

0.338^

0.398^

0.152 0.283#

0.727

\0.001

0.023

0.033#

categorization with the composite outcome. As expected, a statistically significant association was found for categorical SNIP (HR 1.39, 95 % CI 1.07 and 1.81, p = 0.013). Patients with SNIP at baseline \50 cmH2O had a higher risk to experience the composite event than patients with SNIP [70 cmH2O (p value for linear trend \0.001) (Fig. 1). Results of Cox multivariate models are reported in Table 3. In both ‘‘Base’’ and ‘‘Base ? SNIP’’ models, FVC

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Table 2 Univariate Cox regression models for amyotrophic lateral sclerosis patients. Risks are reported as hazard ratios (HR) along with their 95 % confidence interval (95 % CI) Variable

Category

HR

95 % CI

1.023

0.985–1.062

1.000

0.481–2.077

BMI

0.998

0.907–1.099

Charlson Comorbidity Index

0.901

0.636–1.275

0.951

0.911–0.994

Age Sex

Males vs. females

ALSFRSr Site of onset

Spinal vs. bulbar

0.561

0.267–1.180

Disease durationa

0.257

0.047–1.396

FVC

0.986

0.972–1.000

SNIP (categorical)b

1.394

1.073–1.812

SNIP (continuous)

0.975

0.958–0.992

a

Estimated HR for each unitary increase of 5 years in disease duration

b

Estimated HR for each unitary increment in SNIP category [i.e., \30 vs. (30–40), (30–40) vs. (40–50), (40–50) vs. (50–70) and (50–70) vs. C70]

BMI body mass index, ALSFRSr Amyotrophic Lateral Sclerosis Functional Rating Scale revisited, SNIP sniff nasal inspiratory pressure, FVC forced vital capacity

was not statistically associated with the risk of composite event, whereas SNIP was associated to a better outcome (HR 0.98, 95 % CI 0.96–0.99, p = 0.038). At one-year follow-up, the ‘‘Base’’ model yielded a survival c-statistic of 0.84 (95 % CI 0.71–0.97) and a calibration p value of 0.98. The ‘‘Base ? SNIP’’ model, yielded survival c-statistic of 0.91 (95 % CI 0.85–0.96), and calibration p value of 0.99. The p value for the difference between the two survival c-statistics was p = 0.069. The optimal cut-off for SNIP was 34 cmH2O (i.e., patients with SNIP \34 cmH2O

were classified to develop the event within 1 year of follow-up). Such cut-off achieved a sensitivity of 0.75 (95 % CI 0.47–0.91), a specificity of 0.72 (95 % CI 0.63–0.81), a positive predictive value (PPV) of 0.27 (95 % CI 0.12–0.42), a negative predictive value of (NPV) of 0.95 (95 % CI 0.88–0.98). The overall discriminatory power for SNIP was 0.80 (AUC). The discriminatory power for FVC was lower (AUC = 0.57) and the optimal-estimated cutoff was 75.9 (even patients with FVC\75.9 were classified to develop the event within 1 year of follow-up), with a sensitivity of 0.58 (95 % CI 0.32–0.81), a specificity of 0.58 (95 % CI 0.47–0.68), a PPV of 0.16 (95 %CI 0.05–0.27) and a NPV of 0.91 (95 % CI 0.81–0.96). The addition of SNIP into the multivariate model correctly reclassified the risk of the composite events in the 31 % of events and in the 27.2 % of non-events, respectively, achieving a cNRI of 0.58 (p = 0.036). Details of model comparisons are reported in Table 4. Sensitivity analysis for reclassification in terms of cNRI is reported in Supplemental Table 1. The added value of SNIP as predictor is consistently confirmed according to different time horizons for model prediction and non-zero (i.e., more conservative) increase or decrease in reclassification. Figure 2 shows the results of the tree-based RECPAM analysis, where risks of tracheotomy/death was stratified according to SNIP levels, adjusted for global variables (age at the first visit, CCI, and disease duration). Indeed, the algorithm identified three subgroups of patients at different risk for the event. The reference class (Class 3) is represented by the subgroup with the lowest incidence, and all the HRs were estimated with respect to the reference class. A SNIP cutoff value [51 cmH2O identified the reference class (HR = 1), whereas a SNIP cutoff value B18 cmH2O identified the class with the highest risk for the composite event (Class 1, HR 9.85, 95 % CI 2.67–36.29, p \ 0.001).

Fig. 1 Histogram of patients with amyotrophic lateral sclerosis (percentage frequency distribution) within each sniff nasal inspiratory pressure (SNIP) category. The two sets of bars distinguish events and non-events, respectively. Dashed line represents the functional shape of number of events across SNIP values

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Table 3 Multivariate Cox regression models for amyotrophic lateral sclerosis patients Model Base

Variable

Category

HR 1.012

0.971–1.054

Males vs. females

0.864

0.364–2.052

1.052

0.951–1.164

Age Sex BMI Charlson Comorbidity Index

0.850

0.580–1.245

ALSFSr

0.956

0.904–1.011

Site of onset

Base ? SNIP

95 % CI

0.709

0.293–1.716

Disease durationa

Spinal vs. bulbar

0.246

0.040–1.525

FVC

0.995

0.976–1.015

Age

0.999

0.960–1.040

1.009

0.406–2.505

1.064 0.778

0.963–1.175 0.522–1.159

0.970

0.915–1.029

0.562

0.224–1.411

Sex

Males vs. females

BMI Charlson Comorbidity Index ALSFSr Site of onset

Spinal vs. bulbar

Disease duration

a

0.355

0.055–2.300

FVC

1.001

0.980–1.021

SNIP (continuous)

0.977

0.956–0.999

The ‘‘Base’’ model included: age, sex, body mass index (BMI), Charlson Comorbidity index, Amyotrophic Lateral Sclerosis Functional Rating Scale revisited (ALSFSr), forced vital capacity (FVC), site of onset, disease duration, whereas ‘‘Base ? SNIP’’ model further included the sniff nasal inspiratory pressure (SNIP) variable as new predictor. Risks are reported as hazard ratios (HR) along with their 95 % confidence interval (95 % CI) a

Estimated HR for each unitary increase of 5 years in disease duration

Table 4 Discrimination and reclassification measures for event risk prediction in amyotrophic lateral sclerosis patients adding the continuous and the categorical RECursive Partitioning and

AMalgamation (RECPAM) tree-structured sniff nasal inspiratory pressure (SNIP) variable into the clinical-based model, within 1 year of follow-up

Model

Survival c-statistic (95 % CI)

Survival c-statistic difference (p value)

Basea

0.839 (0.708–0.971)

0.069

Base ? SNIP (cont)b

0.907 (0.850–0.963)

Base ? SNIP (tree-str)c

0.911 (0.847–0.974)

Model’s calibration (p value)

cNRI

cNRIevents

cNRI-nonevents

p value

0.977

0.582

0.310

0.272

0.036

0.771

0.352

0.419

0.009

0.996 0.062

0.903

Charlson Comorbidity Index both in Base and Base ? SNIP models was considered as categorical variable a

Base: clinical-based multivariate model which included: age, sex, body mass index, Charlson Comorbidity Index, Amyotrophic Lateral Sclerosis Functional Rating Scale revisited, forced vital capacity, site of onset, disease duration

b

Base ? SNIP (cont): clinical-based multivariate model which further included the continuous SNIP variable Base ? SNIP (tree-str): clinical-based multivariate model which further included the tree-structured SNIP categorical variable, with categories defined from results of RECPAM analysis. SNIP was categorized into the following three classes: Class 1: SNIP B18 cmH2O; Class 2: 18 \ SNIP B51 cmH2O; Class 3: SNIP [51 cmH2O c

Furthermore, SNIP values between 18 and 51 cmH2O identified the intermediate risk class (Class 2, HR 3.53, 95 %CI 1.14–10.91, p = 0.028). Although included as candidate splitting variables into the RECPAM algorithm, sex, ALSFRSr, site of onset, and FVC did not contribute to the identification of further prognostic classes of risk, as

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well as did not enter the final RECPAM model when introduced in a stepwise fashion as main effects. The adjusted survival curves identified by RECPAM were shown in Fig. 3. Most importantly, as shown in Supplemental Table 2, the addition of RECPAM tree-structured SNIP into the ‘‘Base’’ model (i.e., ‘‘Base ? SNIP’’ model)

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better discriminate events from non-events (within 1 year of follow-up) than the continuous SNIP (c-statistic: 0.91, 95 % CI 0.85–0.97) and correctly reclassified the risk of the composite events in the 35.1 % of events and in the 41.9 % of non-events, respectively, achieving a cNRI of 0.77 (p = 0.009) which was greater than cNRI obtained with continuous SNIP. The second RECPAM tree-structured analysis, where SNIP was introduced as determinant variable, did not detect any subgroups of patients for which SNIP had a heterogeneous effect (data not shown). Finally, using only ALS patients with spinal onset of the disease, both univariate (Table 5) and multivariate (Table 6) Cox models showed results mostly overlapping with those reported in the models including the whole sample. Noteworthy, comparing ‘‘Base ± SNIP’’ (categorical tree-structured) vs. ‘‘Base’’ models, even though a

non-significant increase in survival c-statistics (SurvC) have been found (from SurvC = 0.905 to SurvC = 0.907, p = 0.391), a significant cNRI have been achieved (cNRI = 0.653, 95 % CI: -0.090, 1.398, p = 0.042), thus confirming that SNIP was still of greater value over FVC.

Fig. 2 Identification of subgroups of patients with amyotrophic lateral sclerosis (ALS) at different risks for the composite event (tracheotomy or death): results of RECursive Partitioning and AMalgamation (RECPAM) analysis. Figure shows ALS patients with different risks of tracheotomy or death occurrences, based on combinations of key clinical characteristics that were identified by the REPCAM analysis. The tree-growing algorithm estimates hazard ratios from a Cox proportional hazards regression model with sex, Amyotrophic Lateral Sclerosis Functional Rating Scale revisited (ALSFSr), site of the onset, forced vital capacity (FVC), and sniff nasal inspiratory pressure (SNIP) as candidate splitting variables. Age at the first visit, Charlson Comorbidity Index (CCI), and disease duration (for each unitary increase of 5 years) were used as global adjustment variables. Chosen splitting variables are shown between branches, while condition sending patients to left or right sibling is on relative branch. Results were reported as hazard ratios (HR) along with their 95 % confidence interval (95 % CI). Class 3 with the

lowest event rate was reference category (HR = 1). Circles indicate subgroups of patients. Squares indicate patient subgroup RECPAM class. Numbers inside circles and squares represent the number of events (top) and the number of non-events (bottom), respectively. RECPAM results: SNIP was the only and the most important variable for differentiating all risk categories, whereas sex, ALSFSr, site of the onset, and FVC resulted irrelevant for identification of further prognostic classes. SNIP greater than 51 cmH2O identified the reference class (HR = 1), whereas SNIP lower than or equal to 18 cmH2O identified the class with the highest risk for composite event (Class 1, HR = 9.85, 95 %CI: 2.67–36.29, p \ 0.001). Furthermore, SNIP values greater than 18 and lower or equal to 51 cmH2O identified the intermediate risk class (Class 2, HR = 3.53, 95 %CI: 1.14–10.91, p = 0.028). Moreover, although none of the global variables were statistically associated to the composite event, a slight statistical association with the composite event was suggested by CCI (HR = 0.73, 95 %CI: 0.49–1.09, p = 0.121)

Discussion In the present observational study, we showed that SNIP measured at baseline identified ALS patients with early respiratory dysfunction, being a good prognostic indicator of tracheostomy or death within 1 year of follow-up. The optimal cut-off for SNIP was 34 cmH2O and the optimalestimated cut-off for FVC was 75.9 % of predicted value with higher sensitivity and specificity for SNIP compared

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Fig. 3 Adjusted survival curves of patients with amyotrophic lateral sclerosis with respect to each identified RECursive Partitioning and AMalgamation (RECPAM) class (i.e., Class 1: SNIP B18 cmH2O; Class 2: 18 \ SNIP B 51 cmH2O; Class 3: SNIP [51 cmH2O). RECPAM classes were defined as high, medium and low risk for Classes 1, 2, and 3, respectively

Table 5 Univariate Cox regression models for amyotrophic lateral sclerosis patients with spinal onset of the disease Variable

Category

HR

95 % CI

1.034

0.985–1.085

1.309

0.483–3.550

BMI

1.069

0.943–1.213

Charlson Comorbidity Index

1.194

0.796–1.790

Age Sex

Males vs. females

ALSFRSr

0.942

0.884–1.004

Disease durationa

0.187

0.018–1.996

FVC

0.986

0.967–1.006

SNIP (categorical)b

1.510

1.067–2.139

SNIP (continuous)

0.969

0.946–0.992

Risks are reported as hazard ratios (HR) along with their 95 % confidence interval (95 % CI) BMI body mass index, ALSFRSr Amyotrophic Lateral Sclerosis Functional Rating Scale revisited, SNIP sniff nasal inspiratory pressure, FVC forced vital capacity a

Estimated HR for each unitary increase of 5 years in disease duration b Estimated HR for each unitary increment in SNIP category [i.e., \30 vs. (30–40), (30–40) vs. (40–50), (40–50) vs. (50–70) and (50–70) vs. C70]

to FVC. ALS patients with SNIP and FVC at baseline lower than the respective cut-off values were classified as likely to develop tracheostomy or death at one-year

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follow-up. However, the overall discriminatory power for SNIP was higher than FVC (AUC = 0.80 vs. AUC = 0.57). RECPAM analysis identified also subgroups of patients at different risk for the composite event (tracheostomy/death) and SNIP was the only and the most important variable for differentiating all risk categories, whereas sex, ALSFSr, site of onset, and FVC were irrelevant for identification of further prognostic classes. Finally, using only ALS patients with spinal onset of the disease, our findings were mostly overlapping with those reported in the models including the whole sample, thus confirming that SNIP was still of greater value over FVC also in this sub-sample. Population-based studies suggested that bulbar onset disease may be associated with a worse prognosis than spinal onset [4, 24]. In the present study, site of onset appeared not to be a prognostic factor, as also reported in a recent study according to which the site of onset did not influence the risk of early death within 12 months from first diagnosis in ALS patients [25]. However, although not statistically significant, the present findings suggested a better prognosis for subjects with spinal onset of disease. In our cohort, respiratory muscle strength was clearly reduced in ALS patients who still had a normal FVC, according to previous findings indicating impairment of inspiratory muscles [26]. Patients with lower SNIP values at baseline may have a greater benefit from early diagnosis of respiratory dysfunction so clinicians can prompt timely NIV, known to prolong survival in ALS [27]. A positive correlation was recorded between FVC and SNIP values, as found in other studies [28]. SNIP was reported to be the most reliable respiratory test in ALS, combining linear decline, good sensitivity, and high reproducibility in early and advanced stage of the disease [9]. Morgan and colleagues also highlighted the role as predictors of mortality in ALS for both SNIP and FVC prospectively recorded at any point of follow-up [16]. In the present study, SNIP at baseline was significantly associated with the risk of death or tracheostomy in ALS patients, while FVC was not associated with the risk of this composite event. SNIP may be a better marker of respiratory muscle strength in ALS compared to FVC, as it could be performed by patients with advanced disease, providing good prognostic information [16]. In fact, FVC cannot be obtained in about 20 % of the subjects at the later stages of the disease and it was not sensitive to minimal changes in respiratory muscle strength. Nevertheless, FVC is the most commonly applied respiratory parameter and is one of the outcomes measured in ALS clinical trials. Alternative respiratory tests such as maximal inspiratory pressure and maximal expiratory pressure are more sensitive of respiratory muscle weakness than FVC, and have been significantly associated with survival in ALS [15, 29]. These tests are difficult to be

J Neurol (2015) 262:593–603 Table 6 Multivariate Cox regression models for amyotrophic lateral sclerosis patients with spinal onset of the disease without and with sniff nasal inspiratory pressure (SNIP), both as continuous variable (i.e., Model ‘‘Base’’ and ‘‘Base ± SNIP’’, respectively) and SNIP as categorical variable (i.e., ‘‘Base ± SNIP categorical treestructured’’), where SNIP categories were found using RECursive Partitioning and AMalgamation (RECPAM) algorithm. Risks are reported as hazard ratios (HR) along with their 95 % confidence interval (95 % CI)

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Model

Variable

Category

HR

Base

Age

1.013

0.961–1.067

Males vs. females

0.831

0.281–2.461

BMI

1.129

1.000–1.275

Charlson Comorbidity Index

1.207

0.782–1.864

ALSFSr

0.927

0.849–1.012

Sex

a

Base ? SNIP (continuous)

Disease duration

0.280

0.026–2.988

FVC Age

0.996 1.005

0.971–1.022 0.957–1.054

1.028

0.330–3.204

Sex

Base ? SNIP (categorical treestructured)

BMI body mass index, ALSFSr Amyotrophic Lateral Sclerosis Functional Rating Scale revisited, FVC forced vital capacity a

Estimated HR for each unitary increase of 5 years in disease duration

conducted when the bulbar muscles are affected [30], as severe bulbar patients may have upper airway dysfunction, experiencing difficulty in inserting or catching the mouthpiece [31]. SNIP is a short, reliable, voluntary inspiratory maneuver, simple to perform even in severe and bulbar ALS [14], correlating well with invasive and non-volitional tests of diaphragm strength in ALS [13]. SNIP does not require a mouthpiece and involves a natural manoeuver. Indeed, measurements were made at functional residual capacity from end expiratory lung volume with the patients seated comfortably. SNIP is known to predict hypoventilation and hypercapnia with a greater sensitivity than FVC [9, 13], and this test may be a reliable clinical tool to predict also early nocturnal sleep disorders in ALS patients [32]. Previous studies investigated SNIP to predict mortality through the categorization of SNIP measurement into units of 10 cmH2O below 50 cmH2O, with a SNIP \40 cmH2O that was 97 % sensitive for death at 6 months [16]. In a Caucasian population of healthy subjects between 20 and

95 % CI

Males vs. females

BMI

1.110

0.987–1.248

Charlson Comorbidity Index

1.236

0.778–1.964

ALSFSr

0.958

0.875–1.050

Disease durationa

0.562

0.055–5.754

FVC SNIP (continuous)

1.002 0.973

0.976–1.029 0.943–1.003

Age

0.993

0.941–1.047

1.156

0.355–3.762

Sex

Males vs. females

BMI

1.106

0.985–1.242

Charlson Comorbidity Index

1.137

0.709–1.824

ALSFSr

0.970

0.886–1.062

Disease durationa FVC

0.551 0.998

0.046–6.551 0.972–1.024

SNIP: B18 vs. [51

10.085

1.397–72.813

SNIP: (18–51) vs. [51

3.732

0.711–19.595

80 years, SNIP mean values were 91–117 cmH2O for men and 75.5–94 cmH2O for women [33]. In the ATS/ERS statement on respiratory muscle testing, SNIP values [60 cmH2O in women and [70 cmH2O in men were unlikely associated with significant respiratory dysfunction [22]. In the present study, we stratified the risk of death/tracheostomy according to different SNIP levels [16], adjusted for global variables. Two multivariate prediction models have been implemented to evaluate the contribution provided by SNIP in terms of prediction ability, which was assessed both with standard methods (differences in c-statistics) and with the new reclassification measures [23]. Furthermore, with a sophisticated tree-growing technique, we identified different subgroups of patients at different risk for the events tracheostomy/death. A SNIP cutoff value [51 cmH2O identified the group of ALS patients with the lowest risk, whereas a SNIP cutoff value B18 cmH2O identified the group with the highest risk to experience the composite event. A potential limitation of the present study may be represented by the lack of evaluation of SNIP during the follow-

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602

J Neurol (2015) 262:593–603

up. Another limitation may be that the study was conducted in a tertiary care center. In fact, the selection may be a further limitation because patients with older age and bulbar onset are less likely to be referred to a tertiary center of care. In fact, there is a general consensus that older age and bulbar onset are negatively related to ALS outcome [4], and it has been also suggested that patients enrolled in clinical trials from tertiary care centers included younger subjects with a better prognosis [34]. In this study, we evaluated the prognostic role of a respiratory test in ALS patients with RECPAM analysis, already used to study several prognostic factors in patients with lung cancer [35]. Furthermore, the statistical value of this model has been supported by the use of the survival-based cNRI. The addition of SNIP as categories, identified and validated by RECPAM analysis, gave a more significant contribute to improve the discriminatory power of model and the reclassification of the risk, respectively, in the events and non-events (cNRI) when compared with SNIP as continuous value. The present results showed that SNIP is a good prognostic indicator in ALS. Although many years have passed since SNIP has been described for the first time as a viable measure of respiratory muscle strength [12], it is not well known how widespread its application is in clinical practice. To the best of our knowledge, SNIP is used to assess respiratory function primarily in tertiary care centers for ALS, as also suggested by the recent guidelines of the EFNS Task Force on Diagnosis and Management of ALS proposing SNIP as a decisional parameter for beginning NIV (SNIP B40 cmH2O) [36]. The present findings may have several consequences in the multidisciplinary management and planning of symptomatic care of these patients. The evaluation of SNIP in the early phase of ALS may contribute to identify patients with high risk of mortality or intubation. SNIP provides an additional tool for baseline stratification of patients in clinical trials. The early identification of respiratory dysfunction in ALS patients and its prompt and proper treatment could reduce hospitalizations, with important policy implications and reduction of the burden that ALS patients may pose on the National Health Service and healthcare systems worldwide. Acknowledgments This research was supported by European Community’s Seventh Framework Programme (FP7/2007-2013 under grant agreement 259867). Conflicts of interest conflicts of interest.

The authors declare no financial or other

Ethical standard The study has been approved by the Local Ethical Committee and has therefore been performed in accordance with the ethical standards laid down World Medical Association’s 2008 Declaration of Helsinki. All persons gave their informed consent prior to their inclusion in the study.

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Sniff nasal inspiratory pressure as a prognostic factor of tracheostomy or death in amyotrophic lateral sclerosis.

Forced vital capacity (FVC) shows limitations in detecting respiratory failure in the early phase of amyotrophic lateral sclerosis (ALS). In fact, mil...
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