The predictive value of respiratory function tests for non-invasive ventilation in amyotrophic lateral sclerosis

This study was performed at the Radboud university medical centre (Radboudumc) in Nijmegen and the HVS in Utrecht (2 patients switched to another HVS as they moved places; data of these patients were retrieved from their HVS in Groningen and Maastricht).

Inclusion criteria were a diagnosis of definite ALS, according to the El Escorial criteria [19]. We included patients with progressive muscular atrophy (PMA) because of similarities between PMA and ALS regarding clinical course, genetic background and pathology in the spinal cord [20]. For PMA patients, we used criteria that have been described before: progressive lower motor neuron signs and symptoms in 2 or more of the 4 regions (bulbar, cervical, thoracic and lumbar) with careful exclusion of mimics such as multifocal motor neuropathy, and no clinical upper motor neuron signs and symptoms [21].

In addition, two or more respiratory functions tests (FVC, PCF, MIP, MEP or SNIP) had to be assessed at least at the Radboudumc or HVS and at least one daytime capillary blood gas sample had to be taken at the HVS. We excluded patients with a diagnosis of primary lateral sclerosis (PLS), and ALS and PMA patients with severe bulbar impairment or other, physical or cognitive impairments which made the application of NIV impossible, as judged by the referring or HVS physician.

This is a retrospective cohort study. Case records from 2008 up to 2015 were selected. Retrospectively designed studies do not need approval by the local ethics committee. As all tests had been performed for clinical use, there was no need to obtain informed consent. The following data (anonymized by the main researcher) were retrieved:

All tests were performed in the upright position, using a spirometer (Spirostik; Geratherm Bad Kissingen, Germany), a peak flow meter (MicroPeak™; CareFusion, San Diego, USA) or a respiratory pressure meter (Micro RPM™-120; Micro Medical Limited, Rochester, England). All devices are standardized according to the ATS/ERS Statement [22].

Before referral to an HVS, patients are, on average, trimonthly monitored by one of the multidisciplinary ALS care teams. A referral to an HVS is indicated when one or more of the following occurs: FVC <70%, symptoms of nocturnal hypoventilation, signs of increased breathing activity or daytime hypercapnia (PCO₂ > 45 mmHg) [27]. Other respiratory parameters, such as PCF or SNIP, are used infrequently in ALS clinics in Netherlands [4]. At the first HVS assessment, capillary blood gas analysis is performed and an extensive medical history is taken, including signs of nocturnal and daytime hypoventilation. Also, patients are informed about the treatment options: non-invasive ventilation (NIV); invasive ventilation by tracheostomy (TPPV) or palliative care. If a patient opts for ventilatory support in the future, his or her respiratory function will be measured trimonthly at the HVS using the FVC, PCF, MIP, MEP and SNIP to monitor disease progression. Elective NIV indications are made by HVS physicians only. The NIV indication is based on either proven nocturnal or daytime hypercapnia, orthopnoea and/or other complaints of nocturnal or daytime hypoventilation [9, 10].

Patients’ characteristics are reported as proportions and mean ± standard deviation (SD). A time-curve was used to evaluate the decline of the respiratory function tests of patients with two or more consecutive measurements before receiving an NIV indication. Differences in respiratory function tests between 6 months and 3 months before NIV indication and in the latest 3 months were assessed by paired t-tests. To explore the test results of patients who received an NIV indication, the value of the FVC, PCF, MIP, MEP and SNIP was plotted against the cumulative percent of patients with an NIV indication within the following 3 months. Based on these data, tentative cut-off values were determined at an arbitrary value of 85%, with a 95% confidence interval (the value of 15% is a reduction of more than half compared to the proportion of 37% in our previous study and is thought to reflect a clinical relevant difference) [4]. Sensitivity and specificity of these cut-off values, and cut-off values of international guidelines were determined by ROC-curves with the values of t = −3 as positive outcome and values of t = −6 and t = −9 as negative outcome.

Respiratory function test results at the last visit at the ALS clinic of the Radboudumc were compared between two groups, stratified by NIV indication at the first visit at the HVS, using an independent samples t-test, not assuming equal variances (Satterthwaite method).

All five respiratory function tests showed a descending trend between the trimonthly assessments. Average time curves are displayed in Fig. 2a-e. The mean declines within the last 3 months before the NIV indication were 16% ±21(FVC, n = 67), 16% ±19 (PCF, n = 17), 18% ±30 (MIP, n = 64), 13% ±34(MEP, n = 64) and 22% ±28 (SNIP, n = 31), respectively; the difference between t = −3 months and t = NIV indication was significant for all tests (p < 0.001). The difference between t = −6 months and t = −3 months was 16% (FVC; p < 0.001, n = 44), 2% (PCF; p = 0.219, n = 13), 18% (MIP; p < 0.001, n = 43), 17% (MEP; p < 0.001, n = 42) and 15% (SNIP; p < 0.007, n = 15), respectively.

Figure 3a-e shows values of respiratory function tests against the cumulative percentage of patients with an NIV indication within the following 3 months. Cut off values were determined at a value where 85% of the patients received an NIV indication within 3 months, shown in Table 2. Sensitivity and specificity were calculated for these cut-off values (Table 2). In addition, sensitivity and specificity of previously published cut-off values were determined. The ROC curves are shown in Fig. 4a-e.

Out of the 57 patients of the Radboudumc (52% of the 110 included patients), 22 patients received an NIV indication at their first assessment at the HVS and were classified as ‘NIV indication’; 35 other patients were classified as ‘no NIV indication yet’. Table 3 shows the characteristics of these groups. The mean age of the ‘NIV indication’ group was higher (69.8 ± 10.3 years), than the ‘no NIV indication yet’ group (61.4 ± 13.1 years), p = 0.014. In Table 4, the respiratory function tests and complaints (at time of referral) are displayed for groups stratified by NIV indication at the first HVS visit. The time between the last assessment at the ALS clinic and the first visit at the HVS was 6 ± 5 weeks and showed a trend towards a shorter interval in the patients who received an NIV indication compared to the ‘no NIV indication yet’ group (4 ± 3) vs. 7 ± 6; p = 0.056). The mean (SD) PCF was lower in the ‘NIV indication’ group compared to the ‘no NIV indication yet’ group (259 ± 92 L/min vs. 348 ± 135 L/min, p = 0.019). Complaints of nocturnal hypoventilation (assessed at the ALS care team at the Radboudumc) tended to be more frequent in patients with an NIV indication (17 out of 22), compared to the group with no NIV indication yet (18 out of 35), p = 0.051.

Supine FVC has shown the ability to detect diaphragmatic weakness [28] and guidelines suggest that referral to an HVS is indicated when FVC is <70% of the predicted value [27]. Previous cross-sectional studies however, have demonstrated the limitations of the FVC in terms of detection of early respiratory dysfunction (and as such as a criterion for timely referral to an HVS) [4, 11, 12]. One could assume that by using longitudinal data, the FVC may have a better predictive value, however the present retrospective study corroborates the restricted value of FVC to detect imminent respiratory insufficiency, even if serial data are used. Data of the current study show that when using an FVC <70% of the predicted value, 35% of the patients are inadvertently not referred to an HVS within the following 3 months, while they could have benefitted from such a referral [4]. This proportion is comparable to our previous study [4] and are in line with a recent study of Polkey et al., who investigated the predictive value of invasive and non-invasive respiratory muscle strength assessments for survival or ventilator-free survival. The latter study showed a good predictive power of FVC for ventilation-free survival, but the cut off value indicating a poor prognosis, lies within the normal or near normal range (>80% predicted) [29].

As respiratory muscle weakness leads to impaired cough with a lower PCF, we hypothesized that a decline of the PCF may predict the need for NIV in the following months [14]. Indeed, time curves of serial PCF measurements showed a decline of 16% before receiving an NIV indication in the last 3 months. A similar percentage has been found by others who used peak expiratory flow time (PEFT). PEFT increased significantly (indicating more impairment) and linearly with time, 4.7% per month (p < 0.001), which is comparable to our findings (PCF −16% in 3 months = −5.3% per month) [30, 31]. Polkey et al. also showed a descending trend of the peak cough pressure in the months previous to NIV or death [29]. Our data further showed that the PCF, as measured 5.6 weeks before the first HVS assessment, was the only test that discriminated ‘NIV indication’ from ‘no NIV indication yet’ patients. A predictive value of PCF for the need for NIV has been found previously in patients with ALS who had an acute lower respiratory tract infection [16]. Together, our findings and previous findings by others suggest the value of PCF, which should lead to more frequent use of this measure during the respiratory care of patients with ALS [29‐31]. A national survey among referring physicians in the Netherlands suggests room for improvement: PCF was routinely used by half of Dutch ALS physicians (paper in preparation). In a comparable national survey in the UK, the PCF was not included [5].

Patients with an NIV indication were older at the time of referral than the ‘no NIV indication yet’ group. In normal subjects, PCF is generally >500 L/min for all ages [32]. Previous studies showed an (inverse) age effect of the Maximum Expiratory Flow (MEF) and Peak Expiratory Flow (PEF), which was, however, limited when disease effects were excluded [33, 34]. The effect of age on the PCF has been shown in three age groups: 8–15 years, 16–35 years and >36 years; however, we are not aware of an important age effect at ≥60 years [34]. Although we cannot exclude a small effect, it is unlikely that the PCF difference of 89 L/min is due to an age difference.

The difference of the SNIP value between ‘NIV indication’ and ‘no NIV indication yet’ patients was considerable: 28 vs. 40% of the predicted value, although not statistically significant. The latter is probably related to the relatively low number of patients with (serial) SNIP measurements (n = 20 in our study), in particular when we consider previous findings of the SNIP being able to detect hypercapnia, nocturnal hypoventilation or survival in ALS [11, 29, 35, 36]. The significant descent of SNIP values in the months before receiving NIV in our study and (prior to NIV or death) in another study (n = 78) corroborates the importance of SNIP measurements in the clinical assessment of patients with ALS and possible deterioration of respiratory muscle strength [29].

Similarly to the PCF, the SNIP is performed routinely by only a limited number of physicians in the Netherlands (13%; paper in preparation). In the UK 4% of the physicians used the SNIP routinely and 13% of the physicians used SNIP only if patients were symptomatic [5].

The cut-off values that were determined resulted in a high sensitivity to predict an NIV indication within the following 3 months, however specificity was low. This implies that the number of false positive referrals to an HVS is relatively high. However, in our opinion, an early referral is preferable compared to a late referral considering the importance for patients with ALS to make a decision about the possible treatment options. Costs and burden of non invasive respiratory function tests are minimal and compensates the benefit of a timely or even early start of NIV: it has proven to postpone the decrease of respiratory muscle strength and thereby prolong survival [37]. Although bulbar onset can be challenging for NIV to be effective, a recent survey among Dutch referring physicians showed that only 16% stated bulbar impairment as a reason to refrain from referral (paper in preparation). Current practice, at least in the Netherlands, does not exclude these patients form referral to an HVS.

In addition to the strengths of this study (analysis of serial measurements and combining data of an ALS care team and an HVS), one of the limitations is the retrospective design, which is the main reason for the missing values of respiratory function measurements.