Edited by: Costantino Balestra, Haute École Bruxelles-Brabant (HE2B), Belgium
Reviewed by: Jochen D. Schipke, University Hospital of Düsseldorf, Germany; Danilo Cialoni, Dan Europe Foundation, Italy; Kate Lambrechts, Haute École Bruxelles-Brabant (HE2B), Belgium
This article was submitted to Environmental, Aviation and Space Physiology, a section of the journal Frontiers in Physiology
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Acute mountain sickness (AMS) is a potentially life-threatening illness that may develop during exposure to hypoxia at high altitude (HA). Susceptibility to AMS is highly individual, and the ability to predict it is limited. Apneic diving also induces hypoxia, and we aimed to investigate whether protective physiological responses, i.e., the cardiovascular diving response and spleen contraction, induced during apnea at low-altitude could predict individual susceptibility to AMS. Eighteen participants (eight females) performed three static apneas in air, the first at a fixed limit of 60 s (A1) and two of maximal duration (A2–A3), spaced by 2 min, while SaO2, heart rate (HR) and spleen volume were measured continuously. Tests were conducted in Kathmandu (1470 m) before a 14 day trek to mount Everest Base Camp (5360 m). During the trek, participants reported AMS symptoms daily using the Lake Louise Questionnaire (LLQ). The apnea-induced HR-reduction (diving bradycardia) was negatively correlated with the accumulated LLQ score in A1 (
Recreational trekking has become a popular sporting activity, and approximately 40 million people travel to high altitude (HA; ≥3000 m) each year (
Several studies have previously investigated whether individual susceptibility to AMS can be predicted. These studies include a wide range of physiological markers, but with inconsistent findings. For example,
Some investigators have found an association between both the hypoxic ventilatory response (HVR) and the hypercapnic ventilatory response (HCVR) with AMS (
Furthermore, short apneic duration at sea-level has been found to be an independent predictor of AMS (
Apneic diving naturally induces hypoxia, which initiates several protective responses. The cardiovascular diving response (CVD) is initiated by apnea which is enhanced by facial cooling and serves as the first line of defense against hypoxia during apnea, which occurs via sympathetic outflow to peripheral blood vessels leading to vasoconstriction and by parasympathetic outflow to the heart inducing bradycardia (
Accordingly, apneic diving and exposure to altitude are two naturally occurring activities in humans, possibly sharing protective mechanisms against an hypoxic insult. A recent study found that individuals with a pronounced diving response during maximal apnea also maintained higher SaO2 at simulated altitude (
Twenty-two participants, who were already participating in a trekking expedition to mount Everest base camp (EBC; 5360 m), volunteered to participate in the Study. Included in the final analysis were 18 participants; 8 females and 10 males (mean ± SD age was 44 ± 14 years; height: 174 ± 8 cm; weight: 72 ± 12 kg; and vital capacity [VC]: 4.8 ± 0.8 L). Four participants were excluded for taking Acetazolamide which is used to prevent and reduce symptoms of AMS.
Twelve participants had visited HA (≥3000 m) previously, but none in the previous 2 months. Thus, the participants were recreational un-acclimatized trekkers with no prior experience in apneic diving. Human ethical review boards in Sweden and Nepal approved test protocols and all participants gave written informed consent to participate in accordance with the Declaration of Helsinki.
The experimental procedure consisted of two parts: (1) an apnea test conducted in Kathmandu, Nepal, at an altitude of 1400 m and (2) a high altitude trek to EBC.
The participants were asked to report to the lab after at least 1 h without eating or drinking caloric beverages. They entered the lab directly after climbing stairs up to the fourth floor, their height and weight was measured, and they were seated to rest on the chair where the apnea test was conducted and they signed a consent form. Before the apnea test started, after 2 min of seated rest, baseline VC (L) was recorded in duplicate (Vitalograph, Ltd., Compact II, Buckingham England) and the larger volume used for analysis. During the following rest, they received written and oral instructions about the test and after a minimum of 10 min rest, a 2-min countdown for the apnea test started.
The test consisted of three consecutive static apneas in air, with the first at a fixed time limit of 1 min: apnea one (A1), followed by two maximal voluntary duration apneas: apnea two (A2) and apnea three (A3), all of which were separated by 2 min rest (
Timing of apneas (A1: apnea 1; A2: apnea 2; A3: apnea 3) with spleen measure (doted line), continuous measure of SaO2 (arterial oxygen saturation, black line) and HR (heart rate, gray line) and lung volume measures. 15 s of hyperventilation preceded apnea 3 (A3) combined with a MVV (maximal voluntary ventilation) test.
Participants were instructed to exhale fully and take a deep but not maximal breath preceding each apnea, while inspiratory volume was measured. Participants were told to keep the chest relaxed and refrain from swallowing or exhaling during apneas. If SaO2 levels decreased below 60% during apneas, the participants would be told to resume breathing in order not to risk syncope, which may occur below 50% SaO2. Upon termination of apnea, the nose-clip was removed, and the participants were instructed to resume normal breathing. Apneic duration was monitored with a stopwatch.
After 5 min of rest, blood pressure, and forehead temperatures were measured in duplicate to exclude hypertension (200/100) or fever (>38°C). The spirometer were also used for inspiratory and expiratory volumes as well as MVV measurements in the apnea tests. SaO2, HR, partial pressure of end-tidal CO2 and respiratory rate were continuously logged throughout the apnea test, using a combined pulse oximeter-capnograph (Medair Lifesense LS1-9R, Medair AB, Delsbo, Sweden) attached to the middle finger, from two min prior to A1 until 10 min after A3 (
The morning after the apnea test, the participants flew to Lukla (2840 m) and started the EBC trek. They hiked in three groups, organized by a local trekking agency and followed the same ascent profile to Dingboche (4410 m;
Sleeping altitudes for data collection of Lake Louise Questionnaire (LLQ) score (days 1–7) included in the analysis during ascent to EBC (
The LLQ is a self-administered questionnaire consisting of five items quantifying the presence of the most frequent AMS symptoms, including: (1) headache, (2) gastrointestinal symptoms, (3) fatigue, (4) dizziness, and (5) difficulty sleeping. Each item is graded on a scale from 0 (no symptom) to 3 (severe symptom) as described by
The magnitude of the diving response was interpreted through the diving bradycardia which was quantified by the apnea-induced HR-reduction from baseline. Baseline HR was computed by calculating the mean HR (bpm) from 90 to 30 s prior to A1 and used as a reference value. To calculate the mean apnea-induced HR-reduction, the mean HR across the apnea duration, minus the first 30 s (A-30) was computed, thus eliminating the initial tachycardia and decline phase (
Recording of an individual participants diving bradycardia during 1 min apnea. Note the initial tachycardia, followed by a decline phase. The diving response was defined as the percentage reduction in HR (heart rate) during the period from 30 s into the apnea until the end of the apnea, marked as Mean HR, which was compared to the period 90–30 s before the apnea (baseline).
Baseline SaO2 was computed by calculating the mean SaO2 from 90 to 30 s prior to A1. To account for the circulatory delay from the lung to the finger, the arterial O2 desaturation was calculated as the percentage change between baseline SaO2 and the SaO2
Measurements of the maximal splenic length (L), width (W), and thickness (T) were used to calculate spleen volume according to the Pilström equation: V
The formula describes the difference between two ellipsoids divided by two, based on the observed average shape of the spleen (
As all participants followed the same ascent profile to 4410 m, LLQ scores could be summed up to this altitude and used in the analysis. Quantification of AMS symptoms throughout the ascent via the accumulated LLQ score minimizes the influence of the many different conditions that mimic AMS, e.g., exhaustion, dehydration, infection, hangover, migraine and hypoglycemia, which all may lead to some degree of headache (
Data are reported as mean ± SD, except for LLQ data, which are reported as median (range). Normality distribution of the data was assessed using Kolmogorov–Smirnov and Shapiro–Wilk tests (
Apneic duration for A1 was 56 ± 7 s with seven participants not able complete 60 s. The maximal voluntary apnea durations were 70 ± 16 s (range: 35–97 s) for A2 and 92 ± 25 s (range: 55–151 s) for A3.
While most participants reported only mild AMS symptoms, one subject was evacuated by helicopter from 4410 m due to severe AMS. There was an individual variation in accumulated LLQ (0–22) LLQ points with a median score of 9 at 4410 m. Individual apneic durations did not correlate with LLQ score (NS for all apneas).
The mean apnea-induced bradycardia was, for A1: 11 ± 12% (HR
The mean apnea-induced bradycardia was negatively correlated with the LLQ score (
The figures depict correlation plots of accumulated LLQ score at 4410 m and magnitude of the HR (heart rate) reduction (diving bradycardia) during Apnea 1
Resting spleen volume was 191 ± 50 mL (range: 86–261 mL), which was reduced after all apneas, to a mean volume of 160 ± 50 mL (−16%) after A1, 147 ± 36 mL (−23%) after A2 and 149 ± 39 mL (−22%) after A3 (
The spleen volume change after three apneic episodes (apnea 1–3) spaced by 2 min of recovery and the volume after 5 min recovery. ∗∗ indicates
Baseline (resting) spleen volume correlated negatively with LLQ score (
Shows a correlation plot between accumulated LLQ score at 4400 m and baseline (resting) spleen volume
Comparing the differences in diving bradycardia and spleen volume between sub-groups according to their LLQ score, the diving bradycardia during A1 was more pronounced in the Lo group compared to the Hi group (
Shows the magnitude of the heart rate (HR) reduction (diving bradycardia)
Resting SaO2 at low-altitude was 96.3%, which was reduced by 4 ± 1 to 92 ± 2% during A1 (
Shows correlation plots of accumulated LLQ score at 4400 m and arterial O2 desaturation during apnea 1
Resting SaO2 at 4410 m was 79 ± 9% and correlated negatively with LLQ score (
Baseline and functional characteristics of the AMS subgroups based on LLQ score.
Age (years) | 40 ± 15 | 46 ± 17 | 54 ± 7 | 0.177 | 1.2 | −0.1 to 2.3 | 0.484 | 0.4 | −0.8 to 1.5 | 0.365 | 0.6 | −0.6 to 1.7 |
Gender (f;m) | 1;5 | 2;4 | 5;1 | – | – | – | – | – | – | – | – | – |
Height (cm) | 178.2 ± 12 | 173.2 ± 5.5 | 166.8 ± 4.1 | 0.064 | 1.3 | 0.0 to 2.4 | 0.376 | 0.5 | −0.6 to 1.7 | 0.046 | 1.4 | 0.1 to 2.6 |
Weight (kg) | 74.3 ± 13 | 75 ± 12 | 65.6 ± 5 | 0.196 | 0.9 | −0.4 to 2.0 | 0.923 | 0.1 | −1.1 to 1.2 | 0.120 | 1.0 | −0.2 to 2.6 |
Body mass index (kg∗m–2) | 23.2 ± 2 | 24.9 ± 4 | 23.7 ± 3 | 0.770 | 0.2 | −1.0 to 1.3 | 0.342 | 0.5 | −0.7 to 1.6 | 0.498 | 0.3 | −0.8 to 1.5 |
Accumulated LLQ score [median (range)] | 2.5 (0–6) | 9.0 (7–12) | 13.0 (13–22) | 0.0001 | – | – | 0.0006 | – | – | 0.02 | – | – |
Arterial O2 desaturation during A1 (%) | −3.6 ± 1 | −4.2 ± 2 | −5 ± 1 | 0.090 | 1.40 | 0.05 to 2.54 | 0.523 | 0.38 | −0.79 to 1.49 | 0.391 | 0.51 | −0.68 to 1.61 |
Arterial O2 desaturation during A2 (%) | −5.3 ± 3 | −5.5 ± 2 | −8.7 ± 7 | 0.293 | 0.13 | −1.26 to 1,01 | 0.870 | 0.08 | −1.06 to 1.20 | 0.323 | 0.25 | −0.90 to 1.37 |
Arterial O2 desaturation during A3 (%) | −10.7 ± 7 | −6.7 ± 2 | −11.1 ± 7 | 0.965 | 0.04 | −1.17 to 1.09 | 0.221 | 0.78 | −0.45 to 1.88 | 0.224 | 0.85 | −0.39 to 1.96 |
SaO2 at 1400 m (%) | 95.9 ± 2 | 96.9 ± 3 | 96.2 ± 1 | 0.828 | 0.19 | −1.31 to 0.96 | 0.458 | 0.39 | −1.50 to 0.78 | 0.420 | 0.31 | −1.43 to 0.85 |
SaO2 at 4410 m (%) | 86.1 ± 3 | 80.1 ± 6 | 72.3 ± 11 | 0.029 | 1.71 | 0.28 to 2.88 | 0.060 | 1.26 | −0.06 to 2.39 | 0.177 | 0.81 | −0.36 to 1,99 |
HR at 1400 m (bpm) | 75.7 ± 7 | 76.2 ± 9 | 84.9 ± 13 | 0.709 | 0.88 | −1.99 to 0.36 | 0.969 | 0.06 | −1.19 to 1.07 | 0.676 | 0.78 | −0.45 to 1.89 |
HR at 4410 m (bpm) | 78.8 ± 14 | 76.2 ± 14 | 86.2 ± 9 | 0.293 | 0.63 | −1.74 to 0.57 | 0.754 | 0.19 | −0.96 to 1.31 | 0.178 | 0.83 | −0.40 to 1.94 |
VC (L) | 5.1 ± 1 | 4.8 ± 1 | 3.6 ± 1 | 0.008 | 1.50 | 0.12 to 2.64 | 0.507 | 0.30 | −0.86 to 1.41 | 0.031 | 1.20 | −0.11 to 2.32 |
VC (L/cm) | 0.028 ± 0.003 | 0.027 ± 0.004 | 0.021 ± 0.003 | 0.0006 | 2.33 | 0.73 to 3.58 | 0.627 | 0.28 | −0.88 to 1.40 | 0.035 | 1.70 | 0.27 to 2.86 |
Time A1 (seconds) | 56.8 ± 6 | 52 ± 9 | 55.5 ± 7 | 0.725 | 0.20 | −0.95 to 1.32 | 0.298 | 0.63 | −0.58 to 1.73 | 0.472 | 0.43 | −0.74 to 1.54 |
Time A2 (seconds) | 74.3 ± 19 | 61.8 ± 14 | 66.3 ± 12 | 0.413 | 0.91 | −0.34 to 2.02 | 0.232 | 0.50 | −0.68 to 1.61 | 0.578 | 0.35 | −1.46 to 0.82 |
Time A3 (seconds) | 100.3 ± 35 | 84.5 ± 14 | 81.5 ± 17 | 0.279 | 0.68 | −0.53 to 1.79 | 0.345 | 0.59 | −0.61 to 1.70 | 0.748 | 0.19 | −1.31 to 0.96 |
VC was 4.8 ± 1 L and varied between 3 and 6 L. Individual VC correlated negatively with LLQ score (
In the present study we investigated the association between apnea-induced physiological responses with the development of AMS symptoms during a trek to mount Everest base camp (EBC). The principal findings were that: (I) the apnea-induced bradycardia for A1 and A3 was negatively associated with accumulated LLQ score; (II) the apnea-induced bradycardia was also associated with SaO2 at high altitude (HA); (III) resting spleen volume was negatively associated with accumulated LLQ score with ascent.
The finding that the apnea-induced bradycardia is associated with symptoms of AMS suggests that a powerful diving response, which is known to conserve O2 and characterizes successful free divers (
The metabolic rate decreases during apnea through the CVD, which is strongly associated with apneic diving performance (
Several investigations have found an association between AMS and SaO2 measured at HA (
When participants were divided by AMS symptoms, we found a similar pattern that the group who developed most symptoms also desaturated most, whereas the group who developed least AMS symptoms desaturated less and hence were less hypoxic. Interestingly, we found the same pattern in the three LLQ groups for the diving bradycardia. The group who developed less AMS symptoms had the most pronounced apnea-induced bradycardia, followed by the intermediate LLQ group and high LLQ group. This further shows the contribution of the diving response to maintain high SaO2 levels, even in conditions of severe poikilocapnic hypoxia. The low SaO2 in AMS susceptible individuals gives credence to an inefficient O2-conserving effect through a relative marginal diving bradycardia in the etiology of AMS.
The association between the diving bradycardia and AMS symptoms suggests that the initiating mechanism of the diving response shares a common pathway between HA and apneic diving. At HA, a high HVR is associated with superior performance (
A powerful diving response may also reflect a dynamic vascular system, involving a general ability of the body to transiently prioritize blood flow to the most important regions. Endothelial function [flow-mediated dilatation (FMD)] is essential for vasoregulation. At HA, preservation of the vascular system through maintained FMD is crucial for O2 delivery to vital organs. Redistribution of blood flow through peripheral vasoconstriction occurs at HA during exercise, whereby the body down-prioritizes muscle oxygenation (
An additional new finding of the present study is that resting spleen volume is negatively associated with AMS symptoms development, i.e., individuals with larger spleens develop less AMS symptoms. Previous investigations have shown that different hypoxic situations stimulate the spleen to contract and release red blood cells (RBCs), both during apnea (
We hypothesized that the function to increase blood gas transportation capacity would also be efficient at HA, in which a greater spleen volume and ability to contract could be beneficial in coping with HA hypoxia, by enhancing O2-carrying capacity. The findings of an association between individual spleen volume and AMS symptoms supports our hypothesis. The observation is in line with earlier findings in free divers, which suggests that spleen volume was largest in the athletes with the best results in a free diving world championship (
The mechanism by which a large spleen could be protective against AMS is that a higher circulating Hb would enhance blood O2 carrying-capacity, and the larger the spleen, the more RBC can be expelled, which is supported by a strong association between spleen volume and volume contraction in our study. Therefore, an association could also be expected with the maximal volume reduction, however, only a weak tendency was observed in our study. We expected that the participants most sensitive to HA, with the greatest SaO2 reductions at altitude, would have a greater volume contraction. However, there were no association between SaO2 at HA and the magnitude of spleen volume reduction. On the other hand, we found that the group with least AMS symptoms, had both larger resting spleen volume and maximal spleen volume reduction compared to the group who developed most AMS symptoms, indicating the superior contractile function of the bigger spleens, allowing a greater increase in RBC, which is associated with tolerance to HA hypoxia.
We believe this lack of association between spleen volume reduction and AMS symptoms is partly due to the discrepancy between AMS subgroups, i.e., the spleen volume reduction was smaller in the intermediate group compared to the high LLQ group, which was unexpected. Looking at the group with low AMS symptoms, we observe a resting volume of 226 mL, a maximal volume reduction of 77 mL and a pronounced diving response (18% HR-reduction), a clear protective characteristic of HA tolerant individuals resulting in higher SaO2 and subsequently less AMS symptoms. Conversely, the two other groups exhibits smaller and almost similar resting spleen volumes, of 169 and 176 mL, but different volume reduction and levels of SaO2. Presumably, the smaller relative contraction of the intermediate group compared to the Hi group is due to other superior means to cope with hypoxia, e.g., a powerful diving response of 13% HR-reduction, leading to less severe arterial O2 desaturation at HA. Meanwhile, participants who develop more AMS symptoms, exhibit less functional defense systems against hypoxia, e.g., have a smaller magnitude in apnea-induced bradycardia of <3%, leading to more severe arterial O2 desaturation during apnea and at HA. This would thus lead to a stronger/maximal spleen volume contraction, which would thus serve as a second line of defense against hypoxia, and only be triggered maximally if the hypoxia is severe enough. If the spleen were small, however, it would not have as large effect in protecting against hypoxic insult, as the RBC boost into circulation would still be relatively small.
We also found that VC was associated with AMS symptoms development, which has been observed previously (
The current study design is associated with a number of limitations, which should be acknowledged. Although the strength of the study relates to the experimental procedure and establishing a well-functioning laboratory in the field for advanced physiological testing during apnea. A study limitation is that AMS symptoms are self-reported. The LLQ depends solely on individual subjective perception of the occurrence and severity of symptoms (
Although all participants were in the same trekking group, hiking together along the same ascent profile, it may still be difficult to standardize an exact ascent rate, water and food intake and additional drug use, e.g., ibuprofen to relieve headache, factors which may have effects on AMS symptoms development.
SaO2 measurements via pulse oximetry in the field may also have its limitations. This may lead to misinterpretations in certain situations with peripheral vasoconstriction due to cold extremities or hypoxia at HA or during apnea, which may influence the data output (
Furthermore, the low sample size of the current study may also have affected the outcome of the logistic regression model. Therefore, to continue to develop the prediction of AMS susceptibility through this easy-to use and non-invasive apnea test we propose, these results should be further studied in a larger population.
We conclude that the apnea-induced bradycardia and resting spleen volume were inversely associated with AMS symptoms development at HA. These novel findings highlights important links between physiological responses to HA and apneic diving which could contribute to furthering the understanding of the great inter-individual differences in susceptibility to AMS. Measuring individual cardiovascular, splenic and hematological responses induced during apnea at sea-level could possibly be an alternative approach to predict AMS susceptibility in native lowlanders prior to ascent.
The raw data supporting the conclusions of this manuscript will be made available by the authors, without undue reservation, to any qualified researcher.
PH planned and organized the laboratory and field study tests and procedures, collected and analyzed the data, and wrote the manuscript. EM planned and organized the laboratory and field study tests and procedures, collected the data, and proofread the manuscript. AS organized the field laboratory, collected the data, and proofread the manuscript. PL collected the data and proofread the manuscript. ES conceived the idea, planned and organized the laboratory and field study tests and procedures, collected the data, wrote the manuscript, and proofread the manuscript.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
We thank the participants for their efforts, and the people helping us in Nepal, especially Mr. Ram Sapkota (Mountain Delights Treks & Expeditions), Mr. Nicke Sundström (Pathfinder Travel), Mr. Pradeep Pakhrin (Managing Director of Fuji Hotel), and Dr. Arjun Karki (Director of Patan Academy), for their contributions. We acknowledge the International Society for Mountain Medicine Conference in Kathmandu, Nepal in November 2018, where the part of the data was presented and published as an abstract.