Linda E. Keyes

Intrauterine growth restriction, preeclampsia, and intrauterine mortality at high altitude in Bolivia

Infant mortality and stillbirth rates in Bolivia are high and birth weights are low compared with other South American countries. Most Bolivians live at altitudes of 2500 m or higher. We sought to determine the impact of high altitude on the frequency of preeclampsia, gestational hypertension, and other pregnancy-related complications in Bolivia. We then asked whether increased preeclampsia and gestational hypertension at high altitude contributed to low birth weight and increased stillbirths. We performed a retrospective cohort study of women receiving prenatal care at low (300 m, Santa Cruz, n = 813) and high altitude (3600 m, La Paz, n = 1607) in Bolivia from 1996 to 1999. Compared with babies born at low altitude, high-altitude babies weighed less (3084 ± 12 g versus 3366 ± 18 g, p < 0.01) and had a greater occurrence of intrauterine growth restriction [16.8%; 95% confidence interval (CI): 14.9-18.6 versus 5.9%; 95% CI: 4.2-7.5; p < 0.01]. Preeclampsia and gestational hypertension were 1.7 times (95% CI: 1.3-2.3) more frequent at high altitude and 2.2 times (95% CI: 1.4-3.5) more frequent among primiparous women. Both high altitude and hypertensive complications independently reduced birth weight. All maternal, fetal, and neonatal complications surveyed were more frequent at high than low altitude, including fetal distress (odds ratio, 7.3; 95% CI: 3.9-13.6) and newborn respiratory distress (odds ratio, 7.3; 95% CI: 3.9-13.6; p < 0.01). Hypertensive complications of pregnancy raised the risk of stillbirth at high (odds ratio, 6.0; 95% CI: 2.2-16.2) but not at low altitude (odds ratio, 1.9; 95% CI: 0.2-17.5). These findings suggest that high altitude is an important factor worsening intrauterine mortality and maternal and infant health in Bolivia.

Prophylactic low-dose acetazolamide reduces the incidence and severity of acute mountain sickness.

Previous studies have shown low-dose acetazolamide to be effective in preventing AMS in persons already at high altitude and then moving higher, a relatively low risk situation. We wished to evaluate prophylactic administration of low-dose acetazolamide for reducing the incidence and severity of AMS in a high-risk setting: rapid ascent from 1600 to 4300 m. We performed a double-blind, randomized, placebo-controlled study with human subjects (n=44) exposed to 4300 m for 24 h. Subjects were treated for 3 days prior to ascent to 4300 m and during day 1 at altitude with placebo (n=22) or acetazolamide 250 mg/day (125 mg bid, n=22). AMS diagnosis required both an AMS-C score from the Environmental Symptom Questionnaire-III>or=0.7 and a Lake Louise Symptom (LLS) questionnaire score>or=3 plus headache. Acetazolamide reduced the incidence of AMS compared to placebo-treated subjects (14% vs. 45%, respectively, p=0.02), and the number needed to treat was 3. The AMS-C and LLS scores were lower in acetazolamide-treated subjects, indicating less severe AMS. Low-dose acetazolamide administered prior to ascent and on day 1 at 4300 m effectively reduced the incidence and severity of AMS in a high-risk setting.

Effect of K ATP + channel inhibition on total and regional vascular resistance in guinea pig pregnancy

Decreased vascular resistance and vasoconstrictor response during pregnancy enables an increase in cardiac output and regional blood flow to the uterine circulation. We sought to determine whether inhibition of vascular smooth muscle ATP-sensitive potassium ([Formula: see text]) channel activity during pregnancy increased systemic and/or regional vascular resistance and resistance response to ANG II. A total of 32 catheterized, awake, pregnant or nonpregnant guinea pigs were treated with either the [Formula: see text]channel inhibitor glibenclamide (3.5 mg/kg) or vehicle (DMSO) ( n = 8/group). In nonpregnant and pregnant animals, glibenclamide raised blood pressure and systemic, uterine, and coronary vascular resistance, diminishing cardiac output and organ blood flow. Glibenclamide produced a greater rise in coronary vascular resistance in the pregnant than nonpregnant groups and increased renal and cerebral vascular resistance in the pregnant animals only. ANG II infusion raised blood pressure and systemic and renal vascular resistance and lowered cardiac output and renal blood flow in vehicle-treated animals. Glibenclamide augmented ANG II-induced systemic vasoconstriction in the nonpregnant and pregnant groups and the rise in uteroplacental vascular resistance in the pregnant animals. We concluded that [Formula: see text] channel activity likely modulates systemic, uterine, and coronary vascular resistance and opposes ANG II-induced systemic vasoconstriction in nonpregnant and pregnant guinea pigs. Pregnancy augments[Formula: see text] channel activity in the uterine, coronary, renal, and cerebral vascular beds and the uteroplacental circulation during ANG II infusion. Thus increased[Formula: see text] channel activity appears to influence regional control of vascular resistance during guinea pig pregnancy but cannot account for the characteristic decrease in systemic vascular resistance and ANG II-induced systemic vasoconstrictor response.

Pregnancy stimulation of DNA synthesis and uterine blood flow in the guinea pig.

Pregnancy stimulates DNA synthesis in uterine artery smooth muscle cells. Unknown is whether DNA synthesis increases in all layers of the vessel wall in uterine or nonuterine vessels, the distribution and time course of the proliferative response in relation to the rise in uterine blood flow, and the extent to which a pregnancy-induced rise in DNA synthesis can be mimicked by chronic estradiol treatment. To measure DNA synthesis, we implanted bromodeoxyuridine (BrdU, 400 mg) s.c. for 14-d periods in three nonpregnant, nine pregnant, three vehicle, and five estradiol (2.5 mg/14 d)-treated guinea pigs. Uterine blood flow was measured in four nonpregnant and 18 pregnant animals using radiolabeled microspheres. Pregnancy stimulated DNA synthesis in the adventitia, media, and intima of the uterine artery, radial artery (the vessels deriving from the main uterine artery and entering the uterine wall), and uterine vein but not in the aorta or mesenteric artery. Maximal uterine artery medial area and labeling indices in all layers of the uterine artery, uterine vein, and the radial artery adventitia were attained by mid-pregnancy(d 28-42 of the guinea pigs 63-day gestation), whereas DNA synthesis increased progressively until term in the radial artery media and intima. The greatest rise in uterine artery blood flow (y) occurred after peak proliferation in the uterine artery and in concert with radial artery medial and intimal proliferation (y = 1.99·100.023x where x is day postconception). 17β-Estradiol treatment for 14 d in ovariectomized guinea pigs increased DNA synthesis in the radial artery adventitia and tended (p = 0.08) to increase labeling indices in the media of all vessels examined but did not fully reproduce the effects of pregnancy. We concluded that pregnancy-related, possibly hormonal stimuli prompted growth in all layers of the uterine artery wall by mid-pregnancy and served to initiate a rise in uterine blood flow. The resultant increase in flow and shear stress likely stimulated DNA synthesis in the radial artery which helped sustain the rise in flow near term.

Ginkgo biloba Does—and Does Not—Prevent Acute Mountain Sickness

Abstract Objective.—To determine the efficacy of 2 different sources of Ginkgo biloba extract (GBE) in reducing the incidence and severity of acute mountain sickness (AMS) following rapid ascent to high altitude. Methods.—Two randomized, double-blind, placebo-controlled cohort studies were conducted in which participants were treated with GBE (240 mg·d−1) or placebo prior to and including the day of ascent from 1600 m to 4300 m (ascent in 2 hours by car). Acute mountain sickness was diagnosed if the Environmental Symptom Questionnaire III acute mountain sickness–cerebral (AMS-C) score was ≥0.7 and the Lake Louise Symptom (LLS) score was ≥3 and the participant reported a headache. Symptom severity was also determined by these scores. Results.—Results were conflicting: Ginkgo biloba reduced the incidence and severity of AMS compared to placebo in the first but not the second study. In the first study, GBE reduced AMS incidence (7/21) vs placebo (13/19) (P = .027, number needed to treat = 3), and it also reduced severity (AMS-C = 0.77 ± 0.26 vs 1.59 ± 0.27, P = .029). In the second study, GBE did not reduce incidence or severity of AMS (GBE 4/15 vs placebo 10/22, P = .247; AMS-C = 0.48 ± 0.13 vs 0.58 ± 0.11, P = .272). The primary difference between the 2 studies was the source of GBE. Conclusions.—The source and composition of GBE products may determine the effectiveness of GBE for prophylaxis of AMS.

Optic nerve sheath diameter and acute mountain sickness.

OBJECTIVE Increased intracranial pressure (ICP) may contribute to acute mountain sickness (AMS). Measuring optic nerve sheath diameter (ONSD) by ultrasound (US) is a noninvasive technique to detect elevated ICP, and increased ONSD has been associated with AMS. We hypothesized that ONSD would increase with acute, rapid ascent to 4300 m and that increased ONSD would be associated with symptoms of AMS. We further hypothesized that treatment with oxygen at 4300 m would reduce symptoms and ONSD. METHODS A cohort study was performed comparing US measurement of ONSD in healthy subjects at 1400 m and 18 hours after rapid ascent to 4300 m, both before and after oxygen treatment and between subjects with and without AMS (Lake Louise Score ≥3). RESULTS Among 57 subjects, 29 (51%) experienced AMS after rapid ascent to 4300 m. In subjects without AMS, mean ONSD did not increase at 4300 m. In subjects with AMS, mean ONSD increased at 4300 m and was higher than in those without AMS. Treatment with oxygen lowered mean ONSD in subjects with AMS but not in those without AMS. Individual responses to altitude and oxygen varied greatly within groups, and the relationship between ONSD and AMS symptoms was weak. CONCLUSIONS In this controlled study, mean ONSD increased in subjects with AMS at high altitude. However, individual variation was high, and most ONSD values were below the clinical threshold for raised ICP. Observed differences were small, of questionable clinical importance, and within the range of precision of the US machine. Overall, our data do not support a role for increased ICP in mild to moderate AMS.

Ginkgo biloba for Prevention of Acute Mountain Sickness: Does It Work?

Tissot van Patot, Martha, Linda E. Keyes, Guy Leadbetter III, and Peter H. Hackett. Ginkgo biloba for the prevention of acute mountain sickness: does it work? High Alt. Med. Biol. 10:00-00, 2009.-We review the current literature regarding the prophylactic use of Ginkgo biloba extract (GBE) in acute mountain sickness (AMS). We compare studies with regard to GBE dose, composition, study design, altitude reached, ascent rate, exercise, and risk of AMS. We then review what is known about the active components of GBE and their biological effects and apply this knowledge to interpret the results of AMS prevention trials. Overall, the literature suggests that due to the complexity of GBE the standardization of the product is inadequate, which likely explains the disparate clinical results. The variability in commercially available GBE products makes it impossible to determine whether GBE is truly effective for preventing or ameliorating AMS. However, investigating the roles of specific active components of GBE in the prevention of AMS could yield rewards both clinically and in our understanding of the pathophysiology of AMS.

Prophylactic Acetaminophen or Ibuprofen Result in Equivalent Acute Mountain Sickness Incidence at High Altitude: A Prospective Randomized Trial

OBJECTIVE Recent trials have demonstrated the usefulness of ibuprofen in the prevention of acute mountain sickness (AMS), yet the proposed anti-inflammatory mechanism remains unconfirmed. Acetaminophen and ibuprofen were tested for AMS prevention. We hypothesized that a greater clinical effect would be seen from ibuprofen due to its anti-inflammatory effects compared with acetaminophens mechanism of possible symptom reduction by predominantly mediating nociception in the brain. METHODS A double-blind, randomized trial was conducted testing acetaminophen vs ibuprofen for the prevention of AMS. A total of 332 non-Nepali participants were recruited at Pheriche (4371 m) and Dingboche (4410 m) on the Everest Base Camp trek. The participants were randomized to either acetaminophen 1000 mg or ibuprofen 600 mg 3 times a day until they reached Lobuche (4940 m), where they were reassessed. The primary outcome was AMS incidence measured by the Lake Louise Questionnaire score. RESULTS Data from 225 participants who met inclusion criteria were analyzed. Twenty-five participants (22.1%) in the acetaminophen group and 18 (16.1%) in the ibuprofen group developed AMS (P = .235). The combined AMS incidence was 19.1% (43 participants), 14 percentage points lower than the expected AMS incidence of untreated trekkers in prior studies at this location, suggesting that both interventions reduced the incidence of AMS. CONCLUSIONS We found little evidence of any difference between acetaminophen and ibuprofen groups in AMS incidence. This suggests that AMS prevention may be multifactorial, affected by anti-inflammatory inhibition of the arachidonic-acid pathway as well as other analgesic mechanisms that mediate nociception. Additional study is needed.

Outdoor Activity and High Altitude Exposure During Pregnancy: A Survey of 459 Pregnancies

OBJECTIVE To evaluate whether women engage in outdoor activities and high altitude travel during pregnancy; the health care advice received regarding high altitude during pregnancy; and the association between high altitude exposure and self-reported pregnancy complications. METHODS An online survey of women with at least 1 pregnancy distributed on websites and e-mail lists targeting mothers and/or mountain activities. Outcome measures were outdoor activities during pregnancy, high altitude (>2440 m) exposure during pregnancy, and pregnancy and perinatal complications. RESULTS Hiking, running, and swimming were the most common activities performed during pregnancy. Women traveled to high altitude in over half of the pregnancies (244/459), and most did not receive counseling regarding altitude (355, 77%), although a small proportion (14, 3%) were told not to go above 2440 m. Rates of miscarriage and most other complications were similar between pregnancies with and without travel above 2440 m. Pregnancies with high altitude exposure were more likely to have preterm labor (odds ratio [OR] 2.3; 95% CI 0.97-5.4; P = .05). Babies born to women who went to high altitude during pregnancy were more likely to need oxygen at birth (OR 2.34; 95% CI 1.04-5.26; P < .05) but had similar rates of neonatal intensive care unit admission (P = not significant). CONCLUSIONS Our results suggest pregnant women who are active in outdoor sports and travel to high altitude have a low rate of complications. Given the limitations of our data, further research is necessary on the risks associated with high altitude travel and physical activity and how these apply to the general population.

What is wilderness medicine

Defining the field of wilderness medicine can be challenging, particularly for those who do not participate. The founders had a vision of a specialty that incorporates the essentials of practicing medicine in the outdoors without the “luxuries” of a hospital or medical clinic. Rumors abound of the early naming debates— should this group of researchers and practitioners be named the “Wilderness Medical Society,” the “Mountain Medicine Society,” or another, more specific title? Mountain medicine includes high altitude medicine, hypothermia, frostbite, and avalanche injuries, to name a few. Wilderness medicine encompasses mountain medicine, but its scope reaches far beyond. Dive and marine medicine, plant toxinology, animal attacks, and search and rescue all fall within this broad field. Difficult access to patients and environmental extremes are common elements that produce an array of challenges to medical practice. This issue is a tribute to the expansive range of topics that comprise wilderness medicine. Scanning the Table of