Chronic Intermittent Hypoxia and Blood Pressure: Is There Risk for Hypertension in Healthy Individuals?

Abstract

Vinnikov, Denis, Nurlan Brimkulov, and Viktor Krasotski. Chronic intermittent hypoxia and blood pressure: Is there risk for hypertension in healthy individuals? High Alt Med Biol. 17:5–10, 2016.— Aim: The aim of the current study was to assess a year-long impact of chronic intermittent exposure to hypoxia on blood pressure (BP) in healthy working middle-aged adults.

Materials and Methods:

Data from pre-employment and annual screening of high-altitude mining company (elevation 4000 meters above sea level) were obtained for 472 workers aged 34.1 ± 7.8 years, working 2-week shifts, followed by 2 weeks of rest at low altitude (cumulative exposure 6 months). Overall systolic, diastolic BP change (ΔBP) were calculated, and tested in multivariate regression models in the entire group, as well as in different strata of BP.

Results:

Baseline systolic BP reduced from 123.2 ± 11.3 to 116.3 ± 13.1 mmHg (ΔBP 6.8 mmHg), diastolic BP from 76.7 ± 8.4 to 74.9 ± 8.4 mmHg (ΔBP −1.7 mmHg) (p < 0.001), both measured at low altitude before and after one year of exposure to chronic intermittent hypoxia. The greater the baseline BP, the more pronounced was BP decrease. In the most prevalent combined group of normal and high normal BP, both systolic and diastolic BP reduced after one year of high altitude exposure (p < 0.01). In multivariate adjusted models, none of exposures of interest were associated with ΔBP.

Conclusions:

One-year intermittent exposure to hypobaric hypoxia in new hires for high-altitude mining company was not associated with BP increase.

Introduction

Elevated blood pressure (BP) or hypertension is a very prevalent medical condition, and according to Global Burden of Disease, 13.5% of deaths worldwide are due to hypertension (Lim et al., 2013). A number of risk factors have been studied widely, including some occupational exposures, such as working (night) shifts, overtime, stress at work, physical work, and even noise (Van Kempen and Babisch, 2012), and better control of BP is recommended (Mancia et al., 2013). Exposure to hypobaric hypoxia, which is associated with acute rise of BP, may also serve as risk factor for hypertension in a long run, but this has to be confirmed in observational studies.

Current understanding of the impact of high altitude is limited to activation of sympathetic nervous system and catecholamines (Calbet, 2003; Gamboa et al., 2006), which together with other mechanisms result in BP increase when adapting to high altitude. Other mechanisms embrace a range of respiratory, hematological, and neurohumoral effects, such as increase in pulmonary vascular resistance leading to hypoxic pulmonary hypertension, elevated hematocrit, renal and electrolyte responses. People at altitude may be prone to elevated BP also due to increased arterial walls stiffness (Otsuka et al., 2005), and this mechanism has been shown to interact with aging (Parati et al., 2015).

The effect of high altitude, though, may not be homogenous. While the majority of studies shows that subjects develop elevation in blood pressure when transported acutely from low to high altitude (Parati et al., 2014), relatively moderate altitudes may be protective for hypertension (Wang et al., 2015). Obviously, baseline cardiovascular fitness, susceptibility to hypoxia, and age may contribute to systemic BP when measured at altitude. Hypoxia in mining settings at altitude is by itself an occupational exposure, and cardiovascular reactivity is a major contributor to fitness for work at altitude.

Very scarce data exist on long-term observation of healthy workers exposed to chronic intermittent hypoxia as to whether they develop hypertension, since most studies rely on acute exposures. A few studies were conducted in Chilean miners (Richalet et al., 2002; Farias et al., 2006), and in these studies, blood pressure initially increased, followed by a reduction, but remained slightly elevated compared to blood pressure measured at sea level (Farias et al., 2013). Moreover, those studies did not test selected exposures for an association with blood pressure change in regression models.

Therefore, the aim of the current study is to assess the year-long impact of chronic intermittent exposure to hypoxia in a mining setting on BP in healthy working middle-aged adults, and to provide further recommendations for screening and selection based on evidence.

Materials and Methods

Patients and setting

This was a study of the cohort of new hires employed for a gold-mining operation in Tien Shan (Kyrgyzstan) at an average altitude 4000 meters above sea level (MASL). The operation site was an open pit mine, which employed more than 3000 employees with largely dominating Kyrgyz ethnic background, residing either in Bishkek (800 MASL) or in the Issykul plateau (1600 MASL) around the main operation site. Workers commuted to the mine by buses for 2-week shifts, followed by 2-weeks off at home in Issykul or around Bishkek.

Data were collected first on pre-employment screening and then during the next annual screening in one year in a fully licensed and equipped medical clinic in Bishkek at low altitude (800 MASL). Therefore, every subject in the study would have two sets of data. Follow-up examination would typically take place after 1 week of return to the place of residence. Subjects were eventually included in this study only if they were hired for the mine site. Following examination, subjects were exposed to intermittent hypoxia at work for 2 weeks with a subsequent rest at home for 2 weeks. Therefore, their cumulative exposure to intermittent hypoxia was 6 months, with following 6 months of rest at home.

Subjects were hired for various occupations in a mining site: heavy duty vehicles drivers and operators, maintenance personnel (mechanics, lubmen, etc.), kitchen and food handlers, custodial workers, security people, and others. Most people hired to work for the company were expected to have some high-altitude experience. However, subjects were generally healthy and should not have a history of impaired adaptation to altitude conditions in the past, such as high-altitude pulmonary edema or high-altitude cerebral edema. Screening was done on both new hired and continuing personnel, however only new hires in 2009, 2010, and 2011 were included in this analysis.

The medical commission (panel of doctors), comprising nine narrow specialists and one supervisor, operates on a daily basis and performs medical screening of all company employees on a sliding scale (annual screening), as mandated by local Regulation 225 (dated 2011). As of local regulation, anyone employed for high altitude operation, must have annual clearance with a local panel of doctors to exclude contraindications, and presence and severity of detected conditions is reviewed both for high altitude and for a specific post. Such screening comprises physical examination (anamnesis, physical examination), preceded by a set of compulsory tests (blood hemoglobin, white cell count, erythrocyte sedimentation rate, urine test, electrocardiography, vestibular apparatus tests, chest X-ray on employment and every 3 years thereafter, and smear tests in women).

In addition to the mandated tests, this company's screening commission had an extended program for deeper risk assessment, and included additional tests in pre-employment and annual tests profile of employees. This company screening profile set included complete blood count, urine dipstick, venous blood glucose, total cholesterol, lipid profile in all drivers, alanine transaminase, glutathione S-transferase, gamma-glutamyl transpeptidase, urea, creatinine, uric acid, X-ray every year in all, electrocardiography, echocardiography for all on pre-employment, air conductivity hearing test, office spirometry, and night vision test for drivers.

Whenever clinical indication exists, more tests are applied (cardio stress test, bronchodilation test, bone conductivity hearing test, gastroscopy, duplex neck veins scanning, polysomnography, etc.). None of enrolled subjects at baseline examination claimed hypertension in the past or any medication use for this reason. Data for current analysis were extracted from electronic and paper records of such examination. There were no patients with missing data, hence, 100% of those undergoing pre-employment screening in 2009, 2010, and 2011 were included. This study was approved by the Committee on Bioethics of the Kyrgyz State Medical Academy.

Blood pressure measurements

At every visit, BP is measured twice on each subject and were performed in accordance with the existing clinical protocol of the Ministry of Health of Kyrgyz Republic “Clinical protocol: Essential hypertension for primary healthcare level” (dated 2002). When a set of instrumental tests are done in the morning, including ECG, BP is measured by a nurse using calibrated WelchAllyn Tycos sphygmomanometer, and the readings are recorded for a doctor's clinical examination later in the afternoon. BP is also measured in the afternoon at the internist's examination using Korotkov's method on brachial artery with the same WelchAllyn Tycos sphygmomanometer.

Measurements performed by nurses had high reproducibility and equaled doctor's measurements within acceptable limits. This reading is recorded for patient's medical file, both electronically and on paper and guides clinical decisions, as well as copied in a dataset for this analysis. Of note, oxygen saturation in peripheral blood is measured once within the first arrival at mine site using fingertip pulse oxymeter as part of quick clinical “acute stress” examination.

Statistical analysis

Diagnosed conditions, including cardiovascular, were coded to be included into the model. Age and place residence of prospective employees were treated as an independent variable (exposure), both as continuous and categorical. Because we had to reject normality of both systolic and diastolic BP, using Shapiro-Wilk test, only nonparametric tests were used for data analysis, and blood pressure change was tested using Wilcoxon test. Effect modification was tested using stratification approach: subjects were stratified into three groups of baseline systolic BP of optimal (91–120 mm Hg); normal and high normal (121–140 mm Hg); and hypertensive (141 mm Hg and more), based on 2013 ESH/ESC guidelines (Lim et al., 2013). The group of hypotensive subjects was too small (N = 2 with systolic BP 90 mm Hg) to be identified as separate strata.

For other possible confounders, we used direct acyclic diagrams (DAGs) to detect any possible confounding. In multivariate models, variables were adjusted for age, sex, and BMI, whereas there was not enough evidence for job types to serve as confounders. To assess an association between an exposure and an outcome (BP change, both systolic and diastolic) we used multiple regression, and data are presented as crude odds ratios (OR), or adjusted for confounders if stated. Categories were tested with 2X2 (χ²) tables for statistical significance. The null hypothesis of difference between groups was due to chance was rejected when p < 0.05. Data were analyzed using NCSS 9 (Utah, USA) software.

Results

In total, there were 472 subjects, predominantly men, in this study, whose mean age was 34.1 ± 7.8 years with normal mean BP, normal heart rate, and ideal BMI (Table 1). Workers had normal biochemical profiles with slightly elevated hemoglobin with high daily smoking prevalence: 45%. 44% of workers were hired for physically demanding jobs, mainly in maintenance department.

Table 1.

Study Subjects' Profile

Indicators	Values
N	472
Male/female	457/15 (97%/3%)
Lowland residents/Issykul residents	81/391 (17%/83%)
Age, years	34.1 ± 7.8
FVC actual, l	5.2 ± 0.7
FVC % predicted	111.1 ± 12.0
FEV₁/FVC %	80.1 ± 7.6
Height, cm	172.5 ± 6.5
Weight, kg	73.0 ± 12.1
BMI, kg/m²	24.5 ± 3.7
SBP, mm Hg	123.2 ± 11.3
DBP, mm Hg	76.7 ± 8.4
Heart rate, beats per minute	73.0 ± 9.0
Total cholesterol, mmol/L	4.6 ± 1.0
Blood glucose, mmol/L	5.3 ± 0.6
Number of smokers	211 (44.7%)
Cigarettes a day	3.6 ± 5.0
Blood hemoglobin, g/L	171.3 ± 15.6
ESR, mm/h	4.9 ± 5.0
SaO₂ at first ascent, %	88.8 ± 2.8

BMI, body mass index; BP, blood pressure; DBP, diastolic blood pressure; ESR, erythrocyte sedimentation rate; FEV₁, forced expiratory volume during the first second of expiration; FVC, forced vital capacity; SBP, systolic blood pressure. Values are means or percentage ± SD.

Table 2 shows that after 1 year of intermittent exposure to high altitude, BP remained within optimal range in the group. We could not confirm increase in BP throughout the observation, and on overall, there was a reduction of BP compared to baseline as measured a year after the first exposure. Workers categorized into three groups, as shown in Table 2, had similar trends of BP, and subjects in all subgroups of systolic BP had their BP lower a year after first exposure. Most pronounced this reduction was in hypertensive workers: by the end of the first year their BP was normalized.

Table 2.

Systolic BP Change in Groups After One Year of Exposure

	N	Baseline BP, mmHg	BP at 1 year follow-up, mmHg	Δ SBP, mmHg	Δ SBP % to baseline
All	472	123.2 ± 11.3	116.3 ± 13.1^*	−6.8 ± 14.5	−5.0
Group 91–120	230	114.2 ± 7.5	112.5 ± 11.7	−2.2 ± 15.3	−1.6
Group 121–140	233	130.8 ± 5.3	119.4 ± 13.2^*	−11.4 ± 13.9	−8.5
Group 141 and more	9	153.9 ± 6.0	132.9 ± 11.4^*	−21.0 ± 9.0	−13.7

^* p < 0.01 (Wilcoxon test); BP, blood pressure; SBP, systolic blood pressure. Values are means ± SD.

We have also detected similar associations with diastolic ΔBP (Table 3), with relevant increase in BP in those initially hypotensive and reduction of those initially normal or hypertensive. The correlation of BP change with previous high-altitude exposure was not significant.

Table 3.

Diastolic Blood Pressure Change in Groups After One Year of Exposure According to Systolic Blood Pressure Stratification

	N	Baseline BP, mmHg	BP at 1 year follow-up, mmHg	Δ DBP, mmHg	Δ DBP % to baseline
All	472	76.7 ± 8.4	74.9 ± 8.4^*	−1.7 ± 10.0	−1.4
Group 91–120	230	73.3 ± 6.7	73.2 ± 7.3	−0.5 ± 9.9	0.0
Group 121–140	233	79.4 ± 8.0	76.3 ± 8.9^*	−3.1 ± 10.8	−3.1
Group 141 and more	9	90.6 ± 14.0	84.0 ± 12.0	−6.6 ± 17.2	−5.1

^*p < 0.01 (Wilcoxon test); BP, blood pressure; DBP, diastolic blood pressure. Values are means ± SD.

In our subjects we also recorded HR reduction by the end of the first year from 73.0 ± 9.0 to 67.7 ± 8.0 beats per minute. (ΔHR −5.3 ± 11.4, % to baseline −5.9). We tested whether included baseline health indicators could have association with the BP change as an outcome. We performed separate modeling for systolic and diastolic ΔBP. In all subjects, age was associated with systolic BP increase with the OR 1.31 (95% CI 1.11; 1.54), all other included variables, including smoking, were not associated with either systolic or diastolic ΔBP, except FEV₁/FVC in a multivariate model (adjusted for age, sex and BMI) (Table 4).

Table 4.

Predictors of Blood Pressure Change in Bivariate and Multivariate Models

	ΔSBP			ΔDBP
	OR	95% CI	p	OR	95% CI	p
Bivariate models
Age	1.31	1.11; 1.54	0.002	1.05	0.93; 1.18	0.42
Sex	0.83	WCI	0.96	7.29	WCI	0.45
Residence	0.17	WCI	0.32	0.20	0.02; 2.29	0.20
BMI	1.13	0.79; 1.61	0.52	0.66	0.52; 0.84	0.001
FEV₁/FVC	0.93	0.78; 1.10	0.38	1.03	0.92; 1.17	0.58
Smoking	1.74	0.12; 24.6	0.68	0.87	0.14; 5.41	0.88
Hemoglobin	0.97	0.89; 1.06	0.49	0.99	0.94; 1.05	0.85
ESR	1.16	0.90; 1.51	0.26	0.91	0.76; 1.09	0.32
Cholesterol	1.33	0.32; 5.46	0.69	0.83	0.31; 2.22	0.72
Glucose	1.97	0.25; 15.3	0.52	1.87	0.45; 7.72	0.39
Selected multivariate (adjusted models)^*
Smoking	0.95	0.06; 14.3	0.94	0.77	0.12; 5.13	0.72
Cholesterol	0.52	0.11; 2.35	0.41	0.68	0.24; 1.96	0.93
Glucose	0.97	0.12; 7.83	0.98	1.67	0.39; 7.16	0.47

BMI, body mass index; BP, blood pressure; CI, confidence interval; DBP, diastolic blood pressure; ESR, erythrocyte sedimentation rate; FEV₁, forced expiratory volume during the first second of expiration; FVC, forced vital capacity; OR, odds ratio; SBP, systolic blood pressure; WCI, wide confidence interval. ^*Variables adjusted for age, sex, and BMI.

We also separately tested the most prevalent group of systolic BP 121–140. In this group, no variable was associated with diastolic ΔBP, even after adjustment. Conversely, systolic ΔBP was associated with age (crude OR 1.77 (95% CI 1.41; 2.20)) and BMI (crude OR 2.67 (95% CI 1.67; 4.27)). However, no other health indicators, such as blood glucose or cholesterol reached statistical significance in multivariate models.

Discussion

This was a year-long observation of BP in people exposed to intermittent hypoxia at work at altitude 4000 MASL, which showed no increase in BP because of such exposure. Data were obtained on pre-employment and the following annual screening in a central facility at low altitude (800 MASL). In addition, we found various magnitudes of BP change in people with different baseline BP. We found that, when hypotensive subjects are excluded, the higher the baseline BP, the greater was decrease in BP after 1 year. We also found that in the most prevalent subgroup of normal and high normal BP, systolic BP change was associated with age and BMI. Neither smoking nor cholesterol or blood glucose were associated with BP change in multivariate models or made the models very unstable.

The effect of high altitude exposure on BP is a widely discussed scientific issue because of increasing number of people ascending to high altitude for recreation or work. Most studies conclude that exposure to high altitude entails BP increase, as in a cohort of military recruits exposed to high altitude for 12 months (Siques et al., 2009). Also, in native adult highlanders, they reported BP rise similar to dwellers of lowland, and this effect is mediated through lipid metabolism (Tripathy and Gupta, 2007).

Complex interaction of hypoxic conditions with BP is mediated through systemic vasodilatation, increase in blood viscosity via decrease in plasma volume, and opposing increase in hematocrit and also in peripheral resistance growth. This complex association is also mediated via aging mechanisms (Parati et al., 2015), which is highly relevant in an occupational context. However, main focus is made on sympathetic activation and increase in arterial stiffness.

Data on intermittent exposure to high altitude are far less available. Intermittent hypoxia may have different mechanisms of interaction with BP, and our data show that at least 6 months of cumulative exposure during 1 year of employment may not lead to BP increase. Of note, this pattern of exposure differs from those reported in other studies, and comparison with other patterns of exposure is not appropriate.

There are few occupational cohorts with which we could make direct comparisons of our findings. Studies in occupational groups report BP readings shortly after arrival and sometimes few days or, seldom, weeks of exposure. Constructors of the Qinghai–Tibet Railroad also demonstrated normalization and even tendency for decrease of both systolic and diastolic BP over the time of exposure (Wu et al., 2009).

In a smaller study of 50 young military recruits in Chile, they also failed to show elevation in systolic BP after 8 months of stay at high altitude (Siqués et al., 2007). Six months of intermittent exposure of Chilean mine workers did not result in BP increase either (Farias et al., 2006). In a smaller earlier study of 29 healthy miners in Chile, systolic and diastolic BP had a tendency to decline over time (Richalet et al., 2002).

However, none of those studies performed multivariate regression analysis of baseline health indicators with the change of BP as an outcome. Moreover, our study was done as part of a natural process of high-altitude operation, not an experimental exposure of volunteers to intermittent hypoxia. Finally, our study sample is greater than previously reported cohorts, when Qinghai–Tibet Railroad reports are ruled out because of continuous exposure vs. intermittent.

The results of this study demonstrate that the risk associated with elevated BP in intermittent exposure for work may differ from acute exposure pattern in other studies. Acute exposure to high altitude, as described before, leads to three distinct phases of acclimatization with initial unchanged BP because of direct vasodilatory effect counteracting chemoreflex–induced sympathetic activation. This phase then shifts to activation of pressor mechanisms (Hansen and Sander, 2003). In the third phase, there occurs possible inhibition of these mechanisms, and even lower BP readings were obtained from highlanders exposed to hypoxia at altitude (Grocott et al., 2007). In our cohort of healthy middle-aged workers, predominantly men, we probably measured the effect already in the third phase of acclimatization. Nevertheless, the effect may be mediated through confounders, many of which are hard to measure. Though age and BMI were included in the models, some unmeasured confounding, possibly as part of a wide concept of socioeconomic status, may have played a role. This population, once employed, is expected to have much higher and stable income, lower stress level, and better quality of life. Other unmeasured confounding must have also contributed to the “normalizing” effect of exposure.

Other systematic errors worth mentioning for this study are selection and information biases, where the first had a clear representation in a form of “healthy worker” effect. This is a fairly prevalent selection bias in occupational settings, like in the current study, and pre-employment screening with adjacent regulations, as in our case, is what creates such “healthy worker” effect (Li and Sung, 1999). Selection of relatively healthy subjects is inevitable in the real world, because screening procedure is built upon regulations, mandating clearance only to those without serious medical conditions.

Although essential hypertension is not a general contraindication for work at high altitude in Kyrgyzstan, subjects mainly with optimal, normal and high normal BP were selected, because they are assumed to have no serious medical conditions also, and are capable of physical demanding job assignments. Normally “healthy worker” effect would pull the effect measures into the protective range in an exposure-outcome trajectory (Steenland et al., 1996), and we conclude that without this effect the range of BP readings would be wider.

Several ways to reduce the “healthy worker” effect have been proposed, and adjusting for time since hire would be applicable in this type of study; however because of only two points of measurement this method does not seem applicable. This “healthy worker” effect will still be present in almost all types of high-altitude studies, because only certain health groups in general will be likely to expose themselves to high-altitude environment. On the contrary, information bias is unlikely in this study, because exposure itself makes subjects study participants, and outcome misclassification is unlikely when instrumental techniques of BP measurement are enforced.

Study limitations include a short observation period (one year), which is insufficient to show a possible acceleration in vascular aging, no BP repeated measurements at every ascent to work (at work site), and no separate analysis for people admitted to mine site clinic with elevated BP at work. Another limitation of this study is inability to isolate naïve subjects with zero baseline high-altitude exposure, due to traditional life style of ethnic Kyrgyz population. This may explain slightly elevated baseline hemoglobin level in the cohort. One-year observation duration can also be seen as a significant strength of this study, because studies of alien populations at high altitude are usually limited to a period of few days or weeks, and prospective observations are very scarce with small number of subjects.

This study has clear implications for the screening process in an occupational setting. Undoubtedly, BP must be monitored at every visit, and cardiovascular fitness should be given priority; however, conservative approach to BP during pre-employment screening with excessive alertness should be reassessed. Growing evidence of no BP increase in healthy young adults when exposed to intermittent hypoxia implies that after acute phase of acclimatization with BP increase, other mechanisms counterbalancing sympathetic activation are involved. Those should be studied to possibly identify markers of vulnerability to eventually work out methods for easy fitness screening, because clinical decision related to fitness still remains largely subjective with a great extent of uncertainty. Risk related to slightly elevated BP may be exaggerated, and further studies in larger cohorts of young prospective employees should be assessed in longer observational studies.

Conclusion

In conclusion, this prospective observational study of new hires for high-altitude mine at 4000 MASL did not find elevation in BP by the end of the first year of work in conditions of intermittent hypoxia. However, these findings should be generalized with caution and need further confirmation. Guided by the baseline BP, intermittent hypoxia may not necessarily result in BP increase. In our analysis, age and BMI were the only variables associated with change in BP over time in healthy employees for high-altitude operation, and should be considered when making decision related to fitness for work at high altitude.

Footnotes

Acknowledgments

The authors would like to thank all collaborating medical personnel of Kumtor Gold Company medical unit along with the management and personal contribution of medical advisor, Dr. Rupert Redding-Jones. Special gratitude goes to Prof. Paul D. Blanc from the University of California San Francisco for valuable advice.

Author Disclosure Statement

Drs. Vinnikov and Brimkulov do not have any financial conflicts of interest. Dr. Krasovski is a full-time paid employee of Kumtor Gold Company.

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