PHRENIC NERVE CONDUCTION IN HEALTHY SUBJECTS

MARJOLAINE VINCENT, M.D. ,1 ISABELLE COURT-FORTUNE, M.D.,1 FRÉDÉRIC COSTES, M.D. PH.D.,2
JEAN-CHRISTOPHE ANTOINE, M.D. PH.D.,3 and JEAN-PHILIPPE CAMDESSANCHÉ, M.D. PH.D.3
1
Service de Pneumologie et Oncologie Thoracique, CHU St-Etienne, France
2
UCA, INRA UMR 1019, Equipe ASMS, Clermont Ferrand, France
3
Service de Neurologie, CHU St-Etienne, France
Accepted 5 January 2019

ABSTRACT: Introduction: Assessment of diaphragm compound Phrenic nerve stimulation at the sternocleidomas-
muscle action potential by noninvasive phrenic nerve stimulation toid (SCM) muscle is a non-invasive, non-volitional and
at the neck is well described. However, normal values in a large
cohort of healthy subjects are lacking. Our objective was to deter- well tolerated method to assess diaphragmatic function
mine reference values of phrenic nerve conduction in healthy and predict hypoventilation and survival in neuromus-
subjects. Methods: We recruited 155 healthy subjects (25–- cular diseases, especially ALS.3,10,11 Moreover, it has
79 years old) and measured mean amplitude (PhrenAmp) and
latency (PhrenLat) of motor responses according to Bolton’s been shown that percutaneous phrenic nerve stimula-
method. Results: The lower limit for PhrenAmp was 0.28 and tion is easily recordable with fewer adverse events than
0.25 mV and the upper limit for PhrenLat was 8.41 and 8.56 ms diaphragm needle electromyography 12–14
for right and left side, respectively. PhrenLat was correlated with
age. PhrenAmp, PhrenLat and area were significantly higher in Motor responses to non-invasive electrical phrenic
men. Tolerance to phrenic nerve stimulation was excellent. Con- nerve stimulation at the neck have been well described.
clusions: Our study provides normative values of phrenic nerve Changes in mean amplitude of motor responses
motor responses in a large cohort of healthy subjects and iden-
tifies age and sex as factors of variation. (PhrenAmp) is correlated with PFT decline. Con-
Muscle Nerve 59:451–456, 2019 versely, normal PhrenAmp excludes respiratory fail-
ure with high negative-predictive value.3,11 Moreover,
In neuromuscular disorders and especially in amyo- prevalence of increased mean latencies of motor
trophic lateral sclerosis (ALS), respiratory complica- responses or absent motor response is higher in ALS
tions are responsible for most of patient deaths.1 patients15 and correlates with the occurrence of respi-
The onset of diaphragmatic failure precipitates the ratory symptoms, hypoventilation and the decline of
development of hypoventilation.2 However, the forced vital capacity (FVC).10
occurrence of respiratory muscle weakness is fre- Several studies have been conducted to standardize
quently underestimated especially in patients with recording of the amplitude and latency (PhrenLat) of
bulbar paresis who are not able to correctly perform the diaphragm compound muscle action potential
standard pulmonary function tests (PFT).3,4 More- (CMAP) after phrenic nerve stimulation.12,13,16–23
over, PFT are not always closely correlated with trans- However, normal values have been established based
diaphragmatic pressure (Pdi).5–7 The development on a limited number of healthy subjects, and data
of respiratory failure can be predicted from the from a large cohort are lacking. The aim of our study
decrease of spirometric parameters (i.e. vital capac- is to provide reference values of phrenic nerve con-
ity, maximal inspiratory pressure), raised level of duction in a large cohort of healthy subjects.
arterial pressure of carbon dioxide and symptoms.8,9

SUBJECTS
Abbreviations: ALS, amyotrophic lateral sclerosis; BMI, body mass Between October 2014 and May 2015, we prospec-
index; CMAP, compound muscle action potential; FEV1, forced expiratory tively recruited 155 men and women between 25 and
volume at 1 second; MEP, maximum expiratory pressure; MIP, maximum
inspiratory pressure; Pdi, transdiaphragmatic pressure; PFT, pulmonary 79 years of age through newspaper advertisements.
function test; PhrenAmp, amplitude of diaphragmatic response after elec- Inclusion criteria were the absence of confirmed neu-
trical phrenic nerve stimulation; PhrenLat, latency of diaphragmatic
response after electrical phrenic nerve stimulation; PY, pack-year; RET, rological or respiratory diseases. We interviewed all
respiratory endurance test; SNIP, sniff nasal inspiratory pressure; VC, vital potential subjects and excluded those with pregnancy,
capacity
Key words: Phrenic nerve conduction; healthy subjects; normative values neurological or respiratory disorders, major thoracic
Conflicts of interest: None of the authors has any conflict of interest to deformation, or cardiac disease. In uncertain cases,
disclose.
Financial Disclosure: No commercial party having a direct financial inter- we searched for further personal or family history of
est in the results of the research supporting this article has or will confer a respiratory and neurological/neuromuscular disor-
benefit on the authors or on any organization with which the authors are
associated. ders and in some incidences, a respiratory or neuro-
logic clinical examination was done. Pregnancy was
Corresponding author: Marjolaine VINCENT, Service de Pneumologie et
Oncologie Thoracique, Hôpital Nord, CHU Saint Etienne, 42055 SAINT determined based on history alone. The level of physi-
ETIENNE cedex 2, France, Tel.: +33(0)4-77-82-83-14, Fax.: +33(0) cal activity was estimated by interview. Subjects who
4-77-82-80-90, Email: marjolaine.vincent@chu-st-etienne.fr
did endurance activity for at least 30 minutes 3 times
© 2019 Wiley Periodicals, Inc.
Published online 8 January 2019 in Wiley Online Library
a week, were considered as active. The institutional
(wileyonlinelibrary.com). DOI 10.1002/mus.26414 ethical review board of our hospital approved the
Phrenic Nerve Conduction in Healthy Subjects MUSCLE & NERVE April 2019 451
study (ANSM B140667-31) and all the participants PULMONARY FUNCTION TESTS
gave written informed consent. As described in a previous study,24 all subjects
underwent standard PFT and a respiratory endur-
PHRENIC NERVE CONDUCTION ance test (RET) on the same day.
Before neurophysiological study, skin temperature
was measured on the right wrist. Phrenic nerve stim- STATISTICAL ANALYSIS
ulation was performed with a Dantec Keypoint G4 Data analysis was performed using Statistical Pack-
EMG device (Natus, Denmark). Sweep speed was set age for the Social Science (SPSS) v16.0 (IBM,
at 3 ms/division and sensitivity at 0.3 mV/division. USA). Continuous variables were presented as
Diaphragmatic motor responses were assessed by mean and standard deviation (SD). To determine
non-invasive electrical stimulation using a bipolar limits of normal values, we followed the guidelines
electrode positioned at the posterior and inferior established by Dillingham et al. and Chen et al.14,25
border of the SCM muscle, as described previously.19 As the values of CMAP parameters did not follow a
The compound muscle action potential (CMAP) Gaussian distribution, we used the same statistical
was recorded by placing the recording electrode analysis used by Resman-Gaspersc and Podnar.21 The
over the xyphoid process and the reference elec- value of each parameter (PhrenAmp, PhrenLat,
trode over the costal margin 16 cm from the active CMAP area and CMAP duration) was subjected to
electrode on the anterior axillary line. The ground 4 mathematical transformations: natural logarithm
electrode was positioned on the contralateral ante- (ln), Log10, square root and -1/n. For each set of
rior axillary line. Stimulation was performed using transformed data, we estimated skewness and calcu-
square wave pulses of 0.2 to 0.5 ms duration until lated mean  2SD. Finally, we accepted the trans-
supra-maximal stimulation producing “hiccup” sensa- formed data with the least amount of skewness
tion, at the end of the breathing cycle (correspond- (square root) and transformed it back to obtain the
ing to the functional residual capacity-FRC). Subjects normative values. We also calculated the 5th and
were studied in a 45 semi-supine position with the 95th percentiles of each parameter.
neck in a neutral position. The filter was set between Parametric (Pearson) and non-parametric (Spear-
20 Hz and 10 kHz. We selected the response with man) tests were used in order to assess correlations
the highest baseline-to-peak amplitude for each side, for data with normal and non-normal distribution.
after at least 2 supra-maximal stimulations. Latency Multivariate logistic regression was used to evaluate
was measured from the onset of the negative peak. the effect of age, sex, body mass index (BMI), height,
Co-stimulation of the brachial plexus was detected and weight on the electrophysiological data in the dif-
by arm movement and avoided by slight displace- ferent groups of subjects. The level of statistical signifi-
ment of the stimulating electrode. cance was set at P < 0.05. Comparisons between men

Table 1. Characteristics of the subjects studied and results of pulmonary function (mean  SD).
Healthy subjects
Total Men Women Active subjects
N = 155 N = 72 N = 83 N = 51

Age (yrs) (mean  SD) 50.5  14.3 50.6  14.5 50.4  14.2 52.1  13.5
25-34 yrs (n) 25 10 15 6
35-44 yrs (n) 31 17 14 11
45-54 yrs (n) 34 15 19 11
55-64 yrs (n) 37 17 20 14
65-80 yrs (n) 28 13 15 9
Sex (M/W) 71/83 - - 25/26
Weight (kg) (mean  SD) 68.4  13.2 76.5  10,3 61.5  11,5 67.0  11.5
Height (m) (mean  SD) 1.69  0.09 1.76  0.07 1.63  0.06 1.70  0.10
BMI (kg/m2) (mean  SD) 23.9  3.5 24.7  2.9 23.2  3.8 23.2  2.9
Smoker (n; PY) 35; 16 19; 14 19; 17 12; 15
FEV1, L (mean  SD) 3.17  0.7 3.63  0.61 2.77  0.5 3.18  0.80
%pred (mean  SD) 105  13 101  12 109  13 105  11
VC, L (mean  SD) 4.40  0.9 5.10  0.8 3.77  0.6 4.47  1.07
%pred (mean  SD) 119  17 112  14 124  18 120  15
MIP, cmH2O (mean  SD) 84  30 94  28 76  29 95  32
%pred (mean  SD) 89  30 82  24 95  32 101  32
MEP, cmH2O (mean  SD) 120  42 142  38 103  36 128  46
%pred (mean  SD) 82  27 76  23 87  29 80  23
SNIP, cmH2O (mean  SD) 90  25 100  25 88  22 93  26
%pred (mean  SD) 97  24 94  23 99  24 98  24
Predicted MVV (L/min) (mean  SD) 111  24 127  21 97  18 111  28
Cutaneous Temperature ( C) (mean  SD) 31.78  1.86 32.12  1.79 31.49  1.88 31.73  1.88
Dominant side ratio (R/L) 140/14 65/6 75/8 47/4

452 Phrenic Nerve Conduction in Healthy Subjects MUSCLE & NERVE April 2019
 Table 2. Phrenic nerve conduction (mean  SD).
Healthy subjects Total Men Women Active subjects
N = 155 N = 71 N = 83 N = 51

PhrenAmp (mV) (mean  SD) 0.38  0.15 0.45  0.16 0.32  0.11 0.40  0.17
PhrenLat (ms) (mean  SD) 6.59  0.82 6.85  0.76 6.37  0.80 6.52  0.62
CMAP Area (mV*ms) (mean  SD) 3.05  1.51 3.58  1.74 2.93  1.55 3.33  1.82
CMAP Duration (ms) (mean  SD) 16.14  5.80 16.67  7.74 15.86  3.75 15.67  3.24

Table 3. Proposed limits of normal values.

Healthy subjects Total Men Women Active subjects
N = 154 N = 71 N = 83 N = 51

Parameter 5th/95th L/U 5th/95th L/U 5th/95th L/U 5th/95th L/U

PhrenAmp (mV) 0.20/0.69 0.14/0.70 0.27/0.77 0.19/0.78 0.17/0.54 0.13/0.56 0.20/0.78 0.13/0.77
Right PhrenAmp (mV) 0.20/0.72 0.14/0.76 0.28/0.81 0.20/0.83 0.18/0.57 0.13/0.62 0.22/0.80 0.13/0.83
Left PhrenAmp (mV) 0.18/0.64 0.11/0.71 0.21/0.82 0.13/0.84 0.16/0.52 0.11/0.55 0.18/0.76 0.11/0.75
PhrenLat (ms) 5.44/7.98 5.05/8.36 5.75/7.99 5.41/8.56 5.41/7.83 4.88/8.00 5.58/766 5.31/7.81
CMAP Area (mV*ms) 1.56/6.26 0.87/6.61 1.81/7.82 1.03/7.18 1.48/6.57 0.80/5.96 1.39/7.83 0.75/7.15
CMAP Duration (ms) 11.02/22.36 8.31/25.77 11.89/23.31 7.12/29.01 10.96/20.59 9.86/22.44 11.28/20.35 10.34/20.97

5th/95th, 5th/95th percentile limits; L/U, lower/upper limits of normal obtained from transformed data (square root).

and women, active and sedentary subjects, and regression plot of PhrenAmp versus age for both
between active smokers and non-smokers were genders is shown in Figure 1A and 1B. PhrenLat
assessed by unpaired t-test. was found to be significantly correlated with age
(P < 0.001; r = 0.388), height (P < 0.001; r = 0.41),
RESULTS and BMI (P < 0.01; r = 0.25). PhrenAmp was corre-
Subjects’ Characteristics. We included 155 healthy lated with height (P < 0.001; r = 0.31) and, to a
subjects (72 men) aged 25 to 79 years (mean lesser extent, skin temperature (P = 0.018; r = 0.19).
50.5 + 14.3 years). The main characteristics of the PhrenAmp was significantly higher in men (Right
subjects are shown in Table 1. Fifty-one subjects were PhrenAmp P = 0.009; Left PhrenAmp P = 0.02),
considered to be active. We found that skin tempera- whereas PhrenLat was not different between the
ture was significantly related to the BMI (P = 0.003). sexes. After logistic regression analysis adjusted for
No differences were found between the other physi- BMI and age, PhrenAmp and PhrenLat were higher
cal characteristics. in men (P < 0.01). Table 4 summarizes the upper
and lower limits of normal values in subgroups that
Phrenic Nerve Conduction. For all the subjects, were found to be significantly correlated with Phre-
supra-maximal stimulation was obtained with a maxi- nAmp and/or PhrenLat.
mum strength of 10 to 60 mA. In 2 subjects with a The right and left CMAP area was similarly higher
well-muscled neck, no phrenic CMAP could be in men after adjustment for age and BMI (Table 5).
obtained on 1 side. The PhrenAmp and PhrenLat This disappeared after adjustment for age and
results are shown in Table 2, and the upper and height on the right side but not in the left one. No
lower limits of normal are shown in Table 3. A difference was found in PhrenAmp and PhrenLat in

FIGURE 1. Age versus amplitude of response to phrenic nerve stimulation (PhrenAmp) in men (A) and women (B) (graph and
regression line).

Phrenic Nerve Conduction in Healthy Subjects MUSCLE & NERVE April 2019 453
 Table 4. Proposed limits of normal values for PhrenLat according to age, height. and BMI.
Age > 60 Height > 180 cm BMI > 30 kg/m2
N = 50 N = 22 N = 10

Parameter 5th/95th L/U 5th/95th L/U 5th/95th L/U

PhrenAmp (mV) 0.17/0.50 0.15/0.68 0.27/0.59 0.21/0.66 0.23/0.70 0.15/0.70

PhrenLat (ms) 6.11/8.15 5.37/8.60 6.43/8.02 6.13/8.24 5.75/7.95 4.99/8.31

5th/95th, 5th/95th percentile limits; L/U, lower/upper limits of normal obtained from transformed data (square root).

active or former smokers versus nonsmoking subjects previous studies (0.38 mV versus 0.66 m, 0.70 mV,
(P = 0.3). Moreover, PhrenAmp and PhrenLat were and 0.65 mV).20,21,27
not significantly correlated with respiratory muscle We found a slightly lower value of mean CMAP
strength (MIP, MEP, SNIP) and respiratory endur- duration than in the studies of Chen, Resman-Gas-
ance (Tlim). After adjustment for age, sex and persc, and Podnar (16.05 versus 19.4 and 21 ms
height, active people showed no difference com- respectively).20,21 These differences may be explained
pared with sedentary individuals in regard to Phre- by the larger number of participants in our study.
nAmp, PhrenLat, CMAP area and CMAP duration.
We found no significant interside differences for Correlation with Subjects’ Characteristics. PhrenLat
both PhrenAmp and PhrenLat. was significantly related to age. We found that the
Tolerance to phrenic nerve stimulation was excel- upper limit of normal values was higher in subjects
lent and our subjects did not report any adverse 60 years or older. This correlation has been
effect after the test. described in previous studies17,18,20,26,28 and seems to
be linked to axonal loss and disproportionate loss of
DISCUSSION large myelinated fibers with age.20,28 Imai et al sug-
Mean Values and Limits of Normal. The mean Phren- gested that this loss could be a factor of reduced dia-
Lat and upper limit of normal values were shorter phragm strength in the elderly.28
than those reported in some previous studies,12,16,17,26 In our study, PhrenAmp and PhrenLat were signif-
but similar to those found by others.18,20,21,27 Like icantly higher in men and correlated with height.
Chen et al,20 we think that the observed differences The greater height of men could explain the longer
can be explained by differences between sites of stim- PhrenLat, whereas a greater muscle mass, particu-
ulation (at the level of the thyroid or cricoid cartilage larly diaphragm mass, and a larger chest circumfer-
for the former and at a more caudal location just over ence probably explain the difference in PhrenAmp
the clavicle for the latter) and signal recording in this population. According to Resman-Gaspersc
(shorter latencies if recorded from the anterior versus and Podnar, even if no significant correlations were
lateral chest). Moreover, in our study we included a found, the measure of sternum length could be a
large sample of healthy subjects from a wide range of good surrogate measure of phrenic nerve length.21
age, so our results should probably be more generaliz- Moreover, among previous studies, only Resman-
able. In their article, Dillingham et al. recommended Gaspersc and Podnar showed lower mean CMAP
that skin temperature should be maintained between amplitudes and lower limit of normal in women ver-
32 and 36 C.25 In our study, cutaneous temperature sus men, whereas sex differences were not studied
was slightly lower (31.78  1.86). However, it is likely for PhrenLat.21 For Mier et al, PhrenLat was not sig-
not to be of practical importance, because our Phren- nificantly different between the sexes.18 However,
Lat is shorter than those reported by several other most of the studies conducted before 1990 included
authors.12,16,17,26 only men, so data for PhrenAmp and PhrenLat in
We found that PhrenAmp and the corresponding women could not be determined from those early
lower limit of normal were overall lower than in studies.12,26
We did not find great differences in the limits
of normal in subjects taller than 180 cm (see
Table 5. Right-left difference (n = 155). Table 4). The same also applies to obese subjects
Mean  SD Range Mean + 2SD (BMI > 30 kg/m2). While we found that PhrenLat
PhrenAmp (mV) 0.11  0.12 0-0.77 0.34 was significantly correlated with BMI, the limit of
% Difference 10  21 0-108 0.52 normal did not strongly differ from the data
PhrenLat (ms) 0,74  1.05 0-7.42 2.84
% Difference 10  10 0-49 0.30
found in the whole population. This can be
CMAP Area (mV*ms) 0.94  1.19 0-8.20 3.32 explained by the low number of obese subjects
% Difference 10  22 0-122 0.53 (only 10) and also by the fact that this difference
CMAP Duration (ms) 3.12  3.51 0-25.1 10.15
% Difference 18  16 0-82 0.5
disappeared after adjustment for BMI and logistic
regression.
454 Phrenic Nerve Conduction in Healthy Subjects MUSCLE & NERVE April 2019
 Chen et al. found a higher CMAP amplitude in Podnar (3.21 mV*ms versus 8.69) but higher than
ex-smokers, and, in agreement with the result of a those found by Chen et al. (7.28 μV*ms).20,21 We
previous study,20,29 they considered that subclinical found no difference in CMAP area between left
emphysema could explain this difference compared and right sides. However, we did not assess CMAP
with normal subjects. In our study, we included area at different stages of the respiratory cycle. The
55 (22.5%) active or former smokers. In this popula- difference found in right CMAP area in men versus
tion, we found no statistically significant difference women is probably explained by the greater muscle
in PhrenAmp and PhrenLat. However, none of these mass in men.
subjects had significant obstructive respiratory disease
assessed by pulmonary function tests (see inclusion cri- Active Subjects. In our study we found no differ-
teria). Moreover, we did not perform chest X-Ray or ences in phrenic nerve conduction in active subjects
computed tomography, so we are not able to report if compared with inactive ones. This result needs to be
they had objective subclinical emphysema. cautiously interpreted because an objective estima-
In the current study, we found no correlation tion of the subjects’ physical activity level was not
between respiratory muscle strength or endurance available. Further studies are needed in order to
and results of phrenic nerve conduction. Similarly, assess the impact of physical activity on phrenic
Chen et al. found no correlation between spirometry nerve activity, using a more objective evaluation of
results and diaphragmatic responses to phrenic physical activity. Moreover, we did not provide an
nerve stimulation, but only standard spirometric data assessment of muscular mass of the subjects.
were available (total lung capacity, TLC; FEV1).20 In
the study by Mier et al. there was no correlation Limitations. One limitation of this technique could
between conduction time and Sniff Pdi in healthy be inadvertent brachial plexus stimulation, which
subjects and in subjects presenting with respiratory could result in the recording of falsely short laten-
muscle weakness (various neuromuscular diseases).18 cies. This problem can be easily avoided by a more
However, in ALS, Pinto et al. found a significant cor- medial placement of the bipolar electrode.21 The
relation between PhrenAmp and SNIP, and between electrocardiogram could also distort the phrenic
SCM Ampl and MIP, suggesting that the contribu- nerve motor response recording but this problem
tion of diaphragmatic strength was higher for SNIP, can be eliminated by repetition of stimulations.19
and SCM strength higher for MIP.3,30 Moreover,
Stewart et al. found that MIP and MEP did not corre- Implications in Pathology and Future Research. These
late with diaphragm needle EMG.1 Finally, Maran- findings could help physicians to better estimate dia-
hão et al. found a significant correlation between phragm dysfunction in patients with neuromuscular
FEV1, FVC, and inspiratory latencies, but they incor- disease to proactively address the emergence of respi-
rectly assumed that latencies of response to phrenic ratory insufficiency, and to offer them better respira-
nerve stimulation followed a Gaussian distribution, tory monitoring and follow-up. Future research could
so the statistical analysis they used is questionable.27 focus on the impact of skeletal and/or respiratory
All these data suggest that in healthy subjects, respi- muscle training on phrenic nerve responses in neuro-
ratory muscle strength and particularly SNIP also muscular diseases.
depend on the activity of other respiratory muscles.
The authors thank Corinne Court for English reviewing.
In ALS patients, the early involvement of respiratory
muscles leads us to think that diaphragm plays a pre- Ethical Publication Statement: We confirm that we have read the
dominant role in maintaining respiratory muscle Journal’s position on issues involved in ethical publication and
affirm that this report is consistent with those guidelines.
strength.

Right-Left Differences. We did not find significant

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