Relationship between autonomic nervous system function and acute mountain sickness

आऋऑऎऊࣽईࣜऋंࣜ उँऀअࣿࣽईࣜ ࣿऋईईँःँएࣜऋंࣜऌईࣽ Journal of Medical Colleges of PLA 23 (2008) 276–282

www.elsevier.com/locate/jmcpla

Relationship between autonomic nervous system function and acute mountain sickness Long Min1, Huang Lan2, Tian Kaixin2, Yu Shiyong2, Yu Yang2, Qin Jun2* 1

Department of Endocrinology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China 2 Cardiovascular Diseases Research Center, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China Received 4 March 2008, accepted 24 May 2008

Abstract Objective: To elucidate the role of the autonomic nervous system (ANS) in acute mountain sickness (AMS) during the initial phase at acute high-altitude exposure. Methods: Ninety-nine healthy sea-level residents rapidly ascended to Tibet plateau (3 675 m altitude) by airplane from Chengdu plain (560 m altitude). ANS function was tested in plain and day 2–4 in Tibet by heart rate variability (HRV), cold pressor test (CPT). AMS was evaluated by clinic symptomatic scores. All subjects were divided into non-AMS group (57, scores”4) and AMS group (42, scores>4). Results: Compared with non-AMS group, AMS group had higher standard deviation of normal to normal intervals (SDNN), root mean square of delta RR (rMSSD), low-frequency (LF) power, and normalized low-frequency (LFnu) power in plain (P<0.05). After arrival at 3 675 m altitude, AMS group had greater reduction in percentage of delta RR>50 ms(PNN50 ), rMSSD (P<0.01) and SDNN, LF, total power (TP) (P<0.05). Although no significant differences in the increase of SP and DP during CPT were found between 2 groups in plain, the SP increase during CPT of AMS group was less than non-AMS group (P<0.05) at 3 675 m altitude. AMS symptomatic scores was not only positively correlated with SDNN, rMSSD, LF/HF in plain (P<0.05), but also negatively correlated with HFnu in plain (P<0.05). Conclusion: During the initial high altitude exposure, ANS modulation is generally blunted, but the relatively predominant sympathetic control is enhanced, and this characteristic change of ANS function is positively correlated with the development of AMS. Keywords: High altitude; Autonomic nervous system; Acute mountain sickness; Heart rate variability; Cold pressor test

* Corresponding author. Tel.: 86-23-68774625 E-mail address:[email protected] (Qin J.)

Long Min et al. / Journal of Medical Colleges of PLA 23 (2008) 276–282

277

plateau within 90 min. AMS symptomatic scores

1. Introduction

were elevated according to principles of diagnosis and treatment of benign form of acute mountain

Acute mountain sickness (AMS) refers to a

sickness [9] on day 1 in Tibet plateau. Fifty-seven

series of acute reactions in people who acutely

subjects whose scores were 4 or less were divided

ascend from near sea level to altitude higher than

into non-AMS group, while the other 42 subjects

3 000 m [1, 2].Several studies had indicated the

whose scores were higher than 4 were divided into

change

parasympathetic

AMS group. Throughout the study, temperature

activity during high-altitude exposure [3–5]. At

was kept constant at 14–20 ć . Subjects were

high altitude people with high AMS scores

banned to drink coffee or take any medicine.

demonstrated more active sympathetic activity than

Before each measurement, a 15-minute rest was

those with low AMS scores in some degree [6], and

necessary.

of

sympathetic

and

autonomic cardiovascular dysfunction accompanied AMS [7], our experimental study have found

2.2. Observation indexes

high AMS scores people had more obvious decrease of sympathetic and parasympathetic activity [8]. So, we hypothesize that there should be more profound relation between ANS function change and AMS after exposure to plateau field. By means of such techniques as heart rate variability (HRV) measurements and cold pressor test (CPT) to evaluate ANS function, we attempt to compare ANS function of AMS group with that of non-AMS group, reveal the relationship between ANS function change and AMS attack, and provide practical evidences to AMS pathogenesis.

2. Subjects and methods 2.1. Subjects and procedure Ninety nine healthy sea-level male residents (age 19.2±0.96, height 167.00±3.33 cm, and body weight 59.16±5.63 kg) were enrolled in this study. Records were obtained at 560 m altitude (Chengdu plain, Sichuan provinceˈChina) and on day 2–4 at 3 675 m altitude (Tibet plateau, Tibet autonomous region, China) respectively. On the day following the completion of measurement in plain, all subjects were transported by airplane to the Tibet

2.2.1. Heart rate variability (HRV) Analysis of heart rate variability (HRV) is an effective, noninvasive method of assessing the cardiocirculatory system control, by respectively analyzing sympathetic and parasympathetic components of the autonomic nervous system. Five-minute R-R intervals were recorded (Model D/SF-I, Dikang Medical Digital Instrument Co. Ltd, Chengdu, China) in this study. Owing to technique failure, 13 subjects HRV initial data were lost. 86 subjects was measured the short-term HRV respectively in Chengdu plain and on day 2–4 in Tibet plateau successfully in a supine position. Time domain, frequency and non-linear parameters were analyzed by special software. SDNN, one important time domain index, is standard deviation of normal to normal intervals and reflects all the cyclic components responsible for variability in the period of recording. Root mean square of delta RR (rMSSD) and percentage of delta RR>50 ms (PNN 50) were closely related to parasympathetic activity. Power spectrum was obtained by an autoregressive modeling technique. The total power (TP) (0.03–0.40 Hz) is used to estimate of overall autonomic nervous activity. Disagreement

278

Long Min et al. / Journal of Medical Colleges of PLA 23 (2008) 276–282

exists in respect to the Low-frequency (LF) power (0.04–0.15 Hz), most of studies view LF power as

2.3. Evaluation of AMS

reflecting both sympathetic activity and parasympathetic activity. High-frequency (HF) power

Clinical questionnaires were made according

(0.15–0.40 Hz) is regarded as a marker of

to principles of diagnosis and treatment of benign

parasympathetic activity. The representation of LF

form of acute mountain sickness GJB1098-91 [9]

and HF in normalized units (LFnu= LF/[TPíVLF]

and were distributed to all the subjects. Subjects

×100%, HFnu=HF/[TPíVLF]×100%) emphasizes

recorded symptoms in the first evening in Tibet

the controlled and balanced behavior of the two

plateau.

branches of the autonomic nervous system. The LF-to-HF ratio (LF/HF) is considered by some

2.4. Statistical analysis

investigators to mirror sympathovagal balance or to reflect the sympathetic modulations. Fractal dimension (FD), the only non-linear parameter in this study, reflects complex physiological meaning and related to autonomic and central nervous regulations [10].

2.2.2. Cold pressor test (CPT) Because of severe complaints during test and technique failure, 72 subjects’ CPT was successfully performed in Chengdu plain and on day 2 in Tibet plateau respectively. Resting blood pressure was measured in the right upper arm with an electrocardiogram monitor (MP-900F, Nanning Sanqiu Commerce Trade Co, Ltd, China). The left hand below the wrist was immersed in cold water (3 to 5 ć ) for 2 min; blood pressure measurements were obtained at 30, 120, and 300 s after immersion. 2.2.3. Resting blood pressure (BP) and heart rate (HR) All 99 subjects’ resting systolic pressure (SP), diastolic pressure (DP) at the right brachial artery and heart rate (HR) were measured by electrocardiogram monitor (MP-900F, Nanning Sanqiu Commerce Trade Co, Ltd, China) in early morning, in Chengdu plain and on day 2 in Tibet plateau.

Data were analyzed with SPSS10.0 statistical package. Results were expressed as mean±SD. Probabilities of significant differences between high AMS and non-AMS subject groups were obtained by student’s t tests. Differences in the response of each group from plain to Tibet were analyzed

by

paired

sample

tests.

Pearson’s

correlation coefficients were used to determine relationships between AMS score and other variables. A P value of <0.05 was taken as evidence of significance.

3. Results AMS group was significantly higher than non-AMS group in terms of SDNN, rMSSD and LF (P<0.05) in plain, but HFnu was the opposite (P<0.05). After acute exposure to Tibet plateau, no significant differences between the 2 groups were found in HRV parameters (Table 1). But, AMS group displayed a much higher decrease in rMSSD and

PNN 50 [46.15±76.41

vs

2.64±47.88

ms,

(10.77±11.58)% vs (3.91±9.59)%, P<0.01] compared with non-AMS group; SDNN, LF and TP in AMS

group

decreased

significantly,

too

(33.17±55.41 vs 3.77± 32.23 ms, 107.26±198.52 vs 8.98±84.36 ms 2, 317.74± 655.29 vs 46.42±257.77 ms 2, P<0.05).

279

Long Min et al. / Journal of Medical Colleges of PLA 23 (2008) 276–282

Table 1 Comparison of HRV in non-AMS and AMS group in plain and Tibet plateau (mean±SD) non-AMS group

AMS group

(n=49)

(n=37)

1.95±1.19

7.17±2.85 b

í9.307

0.000

SDNN (ms)

54.61±17.16

74.68±49.75

í2.088

0.045

rMSSD (ms)

57.90±24.57

88.32±71.41

í2.206

0.035

Parameters AMS score

PNN 50 (%)

t

P

14.38±9.11

17.25±9.86

í1.262

0.211

2

122.11±77.50

205.12±190.01

í2.228

0.032

2

LF power (ms ) Chengdu plain

HF power (ms )

168.72±115.25

259.80±321.92

í1.460

0.154

HRV

2

TP (ms )

415.75±220.40

615.79±568.08

í1.805

0.080

LFnu (%)

41.53±11.35

44.31±12.44

í0.976

0.332

HFnu (%)

54.91±12.17

47.59±12.44

2.467

0.016

LF/HF

0.85±0.44

1.04±0.60

í1.600

0.114

FD

7.17±1.07

6.59±1.70

1.636

0.109

SDNN (ms)

50.84±28.95

41.51±25.71

1.396

0.167

rMSSD (ms)

55.26±43.40

42.17±38.30

1.309

0.195

PNN 50 (%)

10.47±9.35

6.48±7.29

1.927

0.058

2

113.132±78.38

97.86±75.25

0.820

0.415

2

LF power (ms ) Tibet plateau

HF power (ms )

109.95±102.04

82.50±75.80

1.232

0.222

HRV

2

TP (ms )

369.32±227.47

298.06±277.02

1.187

0.239

LFnu (%)

48.81±17.49

51.76±13.46

í0.765

0.447

HFnu (%)

45.07±16.03

42.54±12.97

0.705

0.483

LF/HF

1.44±1.23

1.42±0.75

0.078

0.938

FD

5.96±1.37

5.68±2.03

0.689

0.493

AMS: acute mountain sickness; HRV: heart rate variability; rMSSD: root mean square of delta RR; PNN50 : percentage of delta RR>50 ms; LF: low-frequency; HF: high-frequency; TP: tota power; LFnu: LF/(TPíVLF)h100%; HFnu: HF/(TPíVLF)h100%; FD: fractal dimension.

In plain, no significant differences in the increase of SP and DP during CPT were found between AMS and non-AMS groups. But at acute exposure to Tibet plateau, the increase in SP during CPT was much less pronounced in AMS group than in non-AMS group (8.44±6.53 vs 12.93±9.46 mmHg, P<0.05). However, no significant differrences were found in the increase of DP in the 2 groups. Compared with baseline, non-AMS group

displayed imperceptible change in the increase of both SP (16.61±11.33 vs 12.93±9.46 mmHg, P>0.05) and DP (13.66±9.16 vs 9.97±7.28 mmHg, P>0.05) during CPT. However, AMS group displayed a more pronounced decrease in the increase of SP during CPT at acute exposure to Tibet plateau (17.56±10.59 vs 8.44±6.53 mmHg, P<0.01), but no significant change was found in DP (12.67 ±8.25 vs 9.74±5.42 mmHg, P>0.05).

280

Long Min et al. / Journal of Medical Colleges of PLA 23 (2008) 276–282

No marked difference between AMS group

suggested AMS group had the lower percentage of

and non-AMS group was found for resting HR and

parasympathetic

BP in plain or Tibet. Compared with baseline, a

Therefore compared with non-AMS group, AMS

marked increase in resting HR was found in non-

group displayed stronger sympathetic activity,

AMS and AMS groups at acute exposure to Tibet

parasympathetic and overall ANS activities as well

plateau (74.55±10.40 vs 96.74±14.95 times/min,

as lower percentage of parasympathetic activity in

75.83±14.50 vs 95.97±11.44 times/min, P<0.01),

ANS activity in plain.

activity

in

ANS

activity.

however, the resting BP change was not significant.

In acute exposure study of 11 subjects to a

There was a marked positive correlation

simulated altitude of 5 000 m by inspiring a

between AMS score and SDNN, rMSSD and

gaseous mixture containing 10.5ˁ oxygen for 30

LF/HF ratio measured in plain (r=0.245, 0.268,

min, those subjects with marked decrease of

0.299; P<0.05). A pronounced negative correlation

rMSSD and significant increase of LFnu and

was found between AMS scores and HFnu

LF/HF demonstrated poor tolerance of hypoxia

measured in plain (r=í0.387, P<0.01). There was

[11]. In a recent study [12] rats were acutely

also a marked positive correlation between AMS

exposed to an altitude of 4 000 m. Those rats

score and the change in rMSSD and SDNN after

preacclimatized to hypobaric hypoxia in a steel

acute exposure to Tibet plateau (r=0.234, 0.255,

chamber (Po 2-100 torr, 4 000 m simulated) for 70 d

P<0.05).

found

changed less in LF, HF and TP after 30 min at an

between AMS score and change in BP during CPT.

altitude of 4 000 m, which suggested stronger ANS

Marked

correlation

was not

modulation in rats have less HRV variation. In the

4. Discussion

same, continual measurement of many HRV parameters in the present study demonstrated a

Our previous study has reported the changes

much higher decrease in rMSSD, PNN50, SDNN,

of ANS function during the initial phase of acute

LF and TP in AMS group at acute high-altitude

exposure to Tibet plateau [3]. The changes include

exposure and less change in BP of AMS group

a transient reduction in sympathetic and para-

during CPT conducted in plateau compared with

sympathetic activities, predominant sympathetic

non-AMS group. Therefore comparison between

control, and generally blunted ANS modulation,

groups showed that people with weak ANS

followed by the slow recovery of ANS function. At

modulation were more predisposed to AMS.

present, it is accepted that people with stronger

In our study, no significant differences

sympathetic activity is riskier at acute high-altitude

between AMS group and non-AMS group were

exposure [6–7].

found for HRV, resting HR and BP on day 2–4 in

The present study revealed that in plain LFnu

Tibet plateau. We didn’t deny if ANS function of

and LF/HF of AMS group were slightly higher than

all subjects everyday was measured on day 1–4 in

those of non-AMS group while LF, rMSSD and

Tibet plateau, marked differences in ANS function

SDNN of AMS group were significant higher.

is found between AMS group and non-AMS group.

These suggested compared with non-AMS group,

Moreover, we supposed ANS change on day 1 in

AMS group may be stronger sympathetic activity

Tibet plateau might be more significant than the

and parasympathetic activity. In addition, the HFnu

following days. Another deficiency of the study

comparison between AMS and non-AMS group

was that it was impossible to exclude subjective

281

Long Min et al. / Journal of Medical Colleges of PLA 23 (2008) 276–282

interference

completely

when

such

clinical

are

predisposed

to

severe

AMS.

HRV

symptoms as headache, vomit, dizziness, etc were

measurements may help predict people susceptible

used to score AMS.

to AMS and screen people who are not predisposed

Up to now, few studies on the correlation

to AMS.

between ANS change and AMS score has been reported. A study showed that after simulated acute

References

high-altitude exposure for 6 h or 12 h plasma catecholamine of AMS group was significantly

1. Savourey G, Guinet A, Besnard Y,et al. Valuation of

higher than that of non-AMS group [6]. The

the Lake Louise acute mountain sickness scoring

present study revealed the correlation between

system in a hypobaric chamber. Aviat Space Environ

AMS score on day 1 in Tibet and HRV parameters

Med 1995; 66 (10): 963–967.

LF/HF, rMSSD, SDNN and HFnu measured in plain. Specifically, AMS score on day 1 in Tibet

2. Basnyat B.The physiologic basis of high altitude diseases. Ann Intern Med 2004; 141 (10): 789–800.

was not only positively correlated with pre-

3. Long M, Qin J, Huang L, et al. Change of autonomic

dominant sympathetic control (LF/HF), para-

nervous system function at the early stage of rapid

sympathetic activity (rMSSD) and overall ANS

entering Tibet plateau. Zhonghua Hang Kong Hang

activities (SDNN), but also negatively correlated

Tian Yi Xue Za Zhi 2006;17(3): 196–199. (In

with relative parasympathetic activity (HFnu), too.

Chinese)

This finding suggested that in plain people with stronger

sympathetic

and

4. Sevre K, Bendz B, Hanko E, et al. Reduced

parasympathetic

autonomic activity during stepwise exposure to high

activities and relatively predominant sympathetic

altitude. Acta Physiol Scand 2001; 173 (4): 409

control would have severe AMS symptoms at acute

–417.

high-altitude exposure. Moreover, the present

5. Cornolo J, Mollard P, Brugniaux JV, et al. Auto-

study also demonstrated the positive correlation

nomic control of the cardiovascular system during

between AMS score and change of rMSSD and

acclimatization to high altitude: effects of sildenafil.

SDNN during acute high-altitude exposure, that

J Appl Physiol 2004; 97 (3): 935–940.

suggested that people with weak ANS modulation

6. Loeppky J.A,Icenogle M.V,Maes D,et al. Body

would have severe AMS symptoms. With reference

temperature,

to the regularity of ANS change before and after

mountain sickness. High Alt Med Biol 2003; 4(3):

acute high-altitude exposure, it can be inferred that

367–373.

autonomic

responses,

and

acute

ANS may play an important role in AMS attack.

7. Lanfranchi PA, Colombo R, Cremona G, et al.

Significant correlation between AMS score and BP

Autonomic cardiovascular regulation in subjects

change during CPT was not found in the present

with acute mountain sickness. Am J Physiol Heart

study. For more factors may interfere with the

Circ Physiol 2005; 289 (6): H2364–H2372.

measurement of ANS function during CPT [13].

8. Long M, Qin J, Huang L, et al. The role of

Briefly, ANS function is related to AMS

autonomic nerve system in the pathogenesis of acute

attack and the severity of the symptoms. In plain

mountain sickness. Jiefangjun Yi Xue Za Zhi 2007;

people

32 (4): 405–408. (In Chinese)

with

strong

sympathetic

and

para-

sympathetic activities and relatively predominant

9. Yin ZY, Xie YZ, Niu WZ, et al. Principles of

sympathetic control and/or weak ANS modulation

diagnosis and treatment of benign form of acute

282

Long Min et al. / Journal of Medical Colleges of PLA 23 (2008) 276–282

mountain sickness. Jiefangjun Yu Fang Yi Xue Za

Hang Tian Yi Xue Yu Yi Xue Gong Cheng 2001; 14

Zhi 1997; 15 (6): 395–399. (In Chinese)

(5): 328–331. (In Chinese)

10. Task Force of the European Society of Cardiology

12. Melin A, Fauchier L, Dubuis E, et al. Heart rate

the North American Society of Pacing Electro-

variability in rats acclimatized to high altitude. High

physiology. Heart Rate Variability Standards of

Alt Med Biol 2003; 4 (3): 375–387.

Measurement,

Physiological

Interpretation,

and

Clinical Use. Circulation 1996; 93 (5): 1043–1065. 11. Liu XX, Lu LL, Zhong CF, et al. Analysis of heart

13. Mitchell LA, MacDonald RA, Brodie EE, et al. Temperature and the cold pressor test. J Pain 2004; 5 (4): 233–237.

rate variability during acute exposure to hypoxia.

(Editor Guo Jianxiu)