Altitude‐Related Hypertension

Two patients have recently been seen in Orange County, CA, for altitude‐related hypertension. Western portions of Orange County, abutting the Pacific Ocean, mostly encompass low‐lying coastal areas with approximately a 50‐meter elevation above sea level. However, some patients who utilize our facilities reside at elevations of 2100 meters in the Big Bear community of the San Bernardino mountains, which is located only 95 km away.

Case 1

A 52‐year‐old white woman taking antihypertensive medications for 2 years complained of elevated blood pressure (BP) at her Big Bear residence compared with BPs that were consistently well controlled with visits to lowland medical clinics. She had been evaluated for hypokalemia associated with the use of triamterene/hydrochlorothiazide and an intentional 7‐kg weight loss. Study results following potassium replacement included a 24‐hour urine free cortisol level of 42.9 μg/24 hours (normal, 4.0–50 μg/24 hours); serum aldosterone 8 ng/dL (normal, ≤28 ng/dL); 24‐hour urine aldosterone 6.1 μg/24 hours (normal, ≤15.6 μg/24 hours); normal fractionated urine metanephrines; a 24‐hour urine sodium level of 171 mmol/24 hours (normal, 40–220 mmol/24 hours); a microalbumin of 31.1 μg/mg cr (normal <30 μg/mg cr); hemoglobin 13.7 g/dL (normal 12–16 g/dL); and a normal noncontrast computed tomography scan of the adrenal glands.

Using a validated home BP apparatus, the patient consistently obtained BPs of 150–180/90–100 mm Hg in the mountains compared with 120–135/70–80 mm Hg in the lowlands. She went to the San Bernardino emergency department on 4 occasions over 6 months for self BPs of 219/122 mm Hg on one occasion and 176/110 mm Hg on another occasion. Repeated BPs in the emergency department on the first occasion declined to 190/70 mm Hg, and she was advised to take clonidine 0.1 mg as needed for BP, which, after 30 minutes, remained either >180 mm Hg systolic or >100 mm Hg diastolic. With clinic follow‐up, she was advised to change her regimen to felodipine 5 mg daily in the lowlands and 10 mg in the mountains and to stop the as‐needed clonidine. In this manner, while BP fluctuations continued, higher BPs with altitude were better controlled.

Case 2

An 80‐year‐old white woman with a validated home BP monitor reported consistently elevated BPs since a move to Big Bear 6 months prior. Lowland clinic BPs had previously been 110–125/60–74 mm Hg. BPs that were consistently 150–158/90–100 mm Hg in the mountains improved to 130/80–85 mm Hg with lisinopril 20 mg daily. However, a follow‐up clinic BP on lisinopril at low altitude was 93/62 mm Hg.

The patient was evaluated by the pulmonary service for chronic obstructive pulmonary disease and increasing dyspnea since she moved to the mountains. She had a 50‐year history of smoking 2 packs a day, quitting 10 years previously. She also had a wedge resection of a T1 stage non–small‐cell lung carcinoma in 2002 without recurrence. When seen in August 2007, pulmonary function tests, which included a forced expiratory volume in 1 second of 1.03 L, 52% predicted (1.99 L), were unchanged compared with preoperative results, and room air oxygen saturation of 96% was unchanged with a 20‐meter walk. Her dyspnea was attributed to her move to 2100 meters, and an increased dose of inhaled bronchodilators was prescribed.

She was advised to take lisinopril 20 mg only in the mornings when she was in the mountains, but was resistant to advice to move back to a lower altitude.

Discussion

Studies of the effects of climate, altitude, and BP are marked by the variability of individual responses and a multitude of interacting variables. In addition to factors that affect BP independently of altitude, such as sodium intake, diet, exercise, body mass index (BMI), and age, increased altitude introduces the additional factors of hypoxia, cold, wind, altitude sickness, dehydration, and stress associated with an environmental change. ¹ Interrelationships between these variables include the positive association between cold climate and increased BMI. ² A higher BMI was believed to be responsible for elevated BPs in high‐altitude (3150 meters) residents of Saudi Arabia compared with low‐altitude (500 meters) dwellers. ³ Mitigating some of these forces are human microenvironments that have been created to shield against some stressors. Individuals can be protected from temperature reductions of about 1°C for each 150 meters of elevation ¹ with warm clothing and heated dwellings, but reduction of barometric pressure with altitude is unprotected.

Another important variable is acclimation vs acclimatization. ² Acclimation is the term used to describe repeated short‐term exposures, such as those used in laboratory studies, and is applicable to the experience described in these 2 cases. Acclimation is the best description of the Orange County, CA, experience of individuals who travel from highland residences to geographically closely approximating lowland medical clinics and other activities, thereby preventing long‐term physiologic accommodation to altitude. Acclimatization refers to long‐term exposure. Acclimation effects occur within a time frame of days to weeks, extending to months, whereas full acclimatization usually takes years. ² The Table summarizes the long‐term (acclimatization) and short‐term (acclimation) effects of climate and altitude on BP.

Table.

 Effects of Climate and Altitude on Blood Pressure (BP)

Variable	Initial Exposure	Short‐Term Acclimation	Long‐Term Residence
Heat
Humid	Decreased BP	Decreased BP	No difference in BP
Dry	Decreased BP	Decreased BP	No difference in BP
Cold
Mild	Increased BP	No difference in BP	No difference in BP
Severe	Increased BP	No difference in BP	Increased BP
Altitude	Increased BP	Increased BP	Decreased BP

Reproduced with permission from Hanna. ²

Long‐term residents and natives of high‐altitude locations generally experience a reduction in BP, as demonstrated in Andean mountain people of South America. Andean residents are also less likely to experience BP elevation with aging. Compared with sea‐level residents, the mountain dwellers are more fit and have less weight, but also consume a high‐sodium diet. Interestingly, Andean dwellers who migrate to low altitude tend to experience an elevation in BP, perhaps related to newly adopted lifestyle patterns with increased weight and reduced exercise. ² Tibetan and Sherpa high‐altitude residents were found to maintain lower BPs than comparable Tibetan migrants to low altitude. ² Again, lifestyle change rather than altitude was thought to account for most of the BP disparity. A study examining BPs of Tibetans displaced to high‐ and low‐altitude communities in India as a result of the Chinese occupation of Tibet showed a consistent age‐related BP difference in the migrants. ⁴ Under the age of 20 years, the Tibetans displaced to higher altitudes in new settlements in India had significantly lower BPs than Tibetans displaced to lower‐altitude settlements. Over the age of 20 years, there was no difference in BP between high‐altitude Tibetans migrating to either high‐altitude or low‐altitude Indian areas, with BP rising with age in both groups. Therefore, both age and lifestyle factors affect long‐term altitude acclimatization.

Elevated BP in response to moving to a higher altitude is a shorter‐term acclimation response predominantly related to the increased autonomic effect of hypoxia. Hyperventilation rapidly assures adequate oxygen delivery, but reduced CO₂ tension continues. Depressed CO₂ acts to inhibit respiration. During the early part of this adaptation, Cheyne‐Stokes breathing, with alternating hyperventilation and hypoventilation may occur, depending on the stronger momentary stimulus. This abnormal breathing pattern may be a stressor causing additional autonomic arousal. ²

A study by Wolfel and colleagues⁵ demonstrated the association between acclimation to high‐altitude and sympathoadrenal activity. Eleven healthy normal‐weight sea‐level residents were transported to Pike’s Peak, CO, at 4300 meters for 3 weeks and administered placebo or propanolol with follow‐up 24‐hour ambulatory BP monitoring and 24‐hour urine collections of norepinephrine. Figure 1 demonstrates (1) the gradual rise in mean arterial pressure beginning on Pike’s Peak at day 2, (2) the variability in individual response to altitude: 2 of 5 individuals in the placebo group did not experience a BP elevation, and (3) that the BP increase still occurred, but was blunted by 240 mg/d of propanolol. Increased heart rate occurred at Pike’s Peak in both the placebo and propanolol groups, although to a lesser extent on β‐blockade. Oxygen desaturation occurred only on day 2, but reduced end‐tidal CO₂ tension was persistent in both groups. Increased norepinephrine excretion, with 24‐hour urine collected on days 2, 8, and 17, was significantly correlated with BP elevation. Urinary norepinephrine excretion was blunted on days 8 and 17 in the propanolol group. Figure 2 shows a similar correlation between elevated supine arterial pressure measurements and elevated venous norepinephrines. ⁶ The main conclusions from these experiments are that the hypertensive effect of high‐altitude acclimation occurs with hyperventilation‐related reduction in end‐tidal CO₂ tension and sympathoadrenal activation. However, there is significant individual variability, and autonomic responsiveness does not completely explain the acclimation response.

Figure 1.

 Daytime mean arterial pressure (MAP) in individual patients receiving (A) placebo (n=5) or (B) propanolol (n=6) at sea level (SL) and at day 2 (PP‐2), day 8 (PP‐8), and day 17 (PP‐17) on Pike’s Peak at 4300 meters. Reprinted with permission from Wolfel et al. ⁵

Figure 2.

 Measurements at sea level and during 20 days on Pike’s Peak (4300 meters). Supine mean arterial pressure measurements as reported in 6 control subjects with venous norepinephrine levels. Reprinted with permission from Reeves et al. ⁶

Competing altitude‐related early acclimation effects on systemic BP include a significant loss of plasma volume and hyperviscosity. Cardiac output may be depressed as much as 24% for the first several days of high‐altitude exposure due to early loss of plasma volume and, in itself, stimulates a relative increase in heart rate. ² Altitude‐related loss of body fluid occurs as a result of hyperventilation, cold‐induced diuresis, and the gastrointestinal effects of high‐altitude illness. Loss of blood volume also causes hemoconcentration with secondary polycythemia and increased blood viscosity, which can increase BP. Contrary direct effects of hypoxia include both systemic vasodilatation ³ and pulmonary hyperventilation due to reduction in nitric oxide synthesis and bioavailability as a result of oxidative stress. ⁷ Race may also effect the adaptation to high altitude. During a 6‐day climb on Kilimanjaro, black Tanzanians did not experience the same BP elevation as the white climbers. ⁸ Competing compensation responses and genetic influences may therefore account for individual variability in the BP response to increased altitude.

What is the altitude threshold used to define BP adaptation to “high altitude”? Although an altitude above 2500 to 3000 meters is generally considered high altitude, a significant plasma noradrenaline response has been described at a more moderate altitude of 1200 meters. ⁹ When 12 healthy young dwellers at 155 meters above sea level in Turkey were moved to a “comfortable” hotel at 1860 meters, significant elevations in systolic and diastolic BP occurred gradually beginning within the first 2 weeks, peaking at about 45 days. These elevations were then sustained with some fluctuation for more than 6 months (Figure 3). ¹ Heart rates that were initially increased gradually subsided so that 5 months following the move, heart rates were decreased below the lower‐altitude baseline. Decreased heart rate with acclimatization was attributed to a down regulation of cardiac β‐adrenergic receptors and/or enhanced parasympathetic activity. ¹

Figure 3.

 Blood pressure (BP) changes at 1860 meters (n=15). All the mean arterial BP and diastolic BP values were significantly different from baseline values ( P<.001). Systolic BP values for all the measurements other than days 105, 120, and 180 were significantly different from baseline values ( P<.001). Baseline measurements were performed at 155 meters. Other measurements were performed at 1860 meters every 15 days. Reprinted with permission from Sizlan et al. ¹

It is uncertain how many Kaiser Permanente patients in Orange County reside in the San Bernardino Mountains and seek regular medical care in lowland clinics. The sparse number of altitude‐related hypertension reports is no doubt multifactorial, due to the small number of at‐risk patients, lack of consideration of altitude‐related BP acclimation unless prompted by patient reports, the complexity of competing compensation variables, and the variability of individual responses. Nonetheless, the degree of BP elevation observed with these 2 cases, >40 mm Hg systolic, is higher than the usually reported maximum acclimation of 20 to 30 mm Hg systolic.

The second case revealed an association between altitude‐related hypertension and altitude‐related hypoxia in an elderly patient with severe obstructive pulmonary disease. As previously noted, the pathophysiology of altitude‐related high BP is primarily related to hypoxia, compensatory hyperventilation, and low CO₂ levels as a result of reduced bariatric pressure.

Wolfel and colleagues⁵ discuss a number of tailored treatment options that are available in addition to β‐blockade. Importantly, all of the studies presented involve experiments and epidemiologic observations of patients with BP elevations but who did not have diagnosed hypertension. Case 1 had diagnosed lowland hypertension with a heightened acclimation BP response to altitude, and case 2 had lowland normotension with sustained hypertension at her new residential elevation of 2100 meters. β‐Blocker monotherapy is no longer recommended as initial therapy for elderly individuals with hypertension in the absence of compelling indications. ¹⁰ The patient in case 1 responded to a titrated calcium channel blocker and the patient in case 2 responded to a titrated angiotensin‐converting enzyme inhibitor. Although specific studies looking at cardiovascular risk associated with altitude‐related hypertension have not been accomplished, a home BP study did show increased cardiovascular mortality associated with large BP fluctuations, ¹¹ similar to those that occurred with traversing from highland to lowland areas in these 2 cases.