"The Bridgnorth Infirmary: Philanthropy, Prejudices and Patients 1832-1948." Midland History, 45(1), pp. 124–125

Retinal venous diameter correlates positively with HAH, adding further evidence for the proposed venous outflow limitation mechanism. The inner layers of the retina swelled disproportionately when compared to the outer layers under conditions of systemic hypoxia. Acetazolamide does not appear to influence altitudinal changes of retinal layers and vasculature.

Objective To assess whether acetazolamide (Az), used prophylactically for acute mountain sickness (AMS), alters exercise capacity at high altitude.Methods Az (500 mg daily) or placebo was administered to 20 healthy adults (aged 36±20 years, range 21–77), who were paired for age, sex, AMS susceptibility and weight, in a double-blind, randomised manner. Participants ascended over 5 days to 4559 m, then exercised to exhaustion on a bicycle ergometer, while recording breath-by-breath gas measurements. Comparisons between groups and matched pairs were done via Mann-Whitney U and Pearson’s χ2 tests, respectively.Results Comparing paired individuals at altitude, those on Az had greater reductions in maximum power output (Pmax) as a percentage of sea-level values (65±14.1 vs 76.6±7.4 (placebo); P=0.007), lower VO2max (20.7±5.2 vs 24.6±5.1 mL/kg/min; P<0.01), smaller changes from rest to Pmax for VO2 (9.8±6.2 vs 13.8±4.9 mL/kg/min; P=0.04) and lower heart rate at Pmax (154±25 vs 167±16, P<0.01) compared with their placebo-treated partners. Correlational analysis (Pearson’s) indicated that with increasing age Pmax (r=−0.83: P<0.005) and heart rate at Pmax (r=−0.71, P=0.01) reduced more in those taking Az.Conclusion Maximum exercise performance at altitude was reduced more in subjects taking Az compared with placebo, particularly in older individuals. The age-related effect may reflect higher tissue concentrations of Az due to reduced renal excretion. Future studies should explore the effectiveness of smaller Az doses (eg, 250 mg daily or less) in older individuals to optimise the altitude–Az–exercise relationships.

INTRODUCTION:The physiological responses on exposure to high altitude are relatively well known, but new discoveries are still being made, and novel prevention and treatment strategies may arise. Basic information has changed little since our previous review in this journal 10 years ago, but considerable more detail on standard therapies, and promising new approaches are now available.AREAS COVERED:Herein, the authors review the role of pharmacological agents in preventing and treating high-altitude illnesses. The authors have drawn on their own experience and that of international experts in this field. The literature search was concluded in March 2018.EXPERT OPINION:Slow ascent remains the primary prevention strategy, with rapid descent for the management of serious altitude illnesses. Pharmacological agents are particularly helpful when rapid ascent cannot be avoided or when rapid descent is not possible. Acetazolamide remains the drug of choice for prophylaxis of acute mountain sickness. However, evidence indicates that reduced dosage schemes compared to the current recommendations are warranted. Calcium channel blockers and phosphodiesterase inhibitors remain the drugs of choice for the management of high-altitude pulmonary edema. Dexamethasone should be reserved for the treatment of more severe cases of altitude illnesses such as cerebral edema.

Rapid ascent to high altitude commonly results in acute mountain sickness, and on occasion potentially fatal high-altitude cerebral edema. The exact pathophysiological mechanisms behind these syndromes remain to be determined. We report a study in which 12 subjects were exposed to a FiO(2) = 0.12 for 22 h and underwent serial magnetic resonance imaging sequences to enable measurement of middle cerebral artery velocity, flow and diameter, and brain parenchymal, cerebrospinal fluid and cerebral venous volumes. Ten subjects completed 22 h and most developed symptoms of acute mountain sickness (mean Lake Louise Score 5.4; p < 0.001 vs. baseline). Cerebral oxygen delivery was maintained by an increase in middle cerebral artery velocity and diameter (first 6 h). There appeared to be venocompression at the level of the small, deep cerebral veins (116 cm(3) at 2 h to 97 cm 3 at 22 h; p < 0.05). Brain white matter volume increased over the 22-h period (574 ml to 587 ml; p < 0.001) and correlated with cumulative Lake Louise scores at 22 h (p < 0.05). We conclude that cerebral oxygen delivery was maintained by increased arterial inflow and this preceded the development of cerebral edema. Venous outflow restriction appeared to play a contributory role in the formation of cerebral edema, a novel feature that has not been observed previously.

Rapid ascent to high altitude can result in high altitude headache, acute mountain sickness, and less commonly, high altitude cerebral or pulmonary edema. The exact mechanisms by which these clinical syndromes develop remain to be fully elucidated. Direct and indirect measures of intracranial pressure (ICP) usually demonstrate a rise in pressure when human subjects and animals are exposed to acute hypoxia. However, the correlation of ICP changes to symptoms and altitude-related illnesses has been difficult to establish. Headache, for example, may occur with vessel distension prior to a rise in ICP. This article reviews the literature both supporting and refuting an increase in ICP as the underlying mechanism of headaches and other related neurological sequelae experienced at high altitude.

OBJECTIVE:To assess the effect of acetazolamide (Az) on exercise performance during early acclimatization to altitude. METHODS:Az (250 mg twice daily) or placebo was administered for 3 days in a double-blind, randomized manner followed by a rapid ascent to 3459 m in the Italian Alps. Twenty healthy adults (age range, 18-67 years) were tested at 60% of sea-level peak power output for 15 minutes on a bicycle ergometer after 16 to 27 hours of altitude exposure. Exercise performance was measured in relation to peripheral oxygen saturations measured from pulse oximetry (Spo2), Lake Louise acute mountain sickness (AMS) score, and perceived difficulty. RESULTS:At altitude, resting Spo2 was higher in the Az group compared with placebo (P < .001). The highest AMS scores were in 4 of the placebo individuals with the lowest resting Spo2 (P < .05). During the exercise test, Spo2 fell in all but 1 subject (P < .001) and was reduced more in the Az group (P < .01). Four Az and 1 placebo subject were unable to complete the exercise test; 4 of these 5 had the largest fall in Spo2. The perception of exercise difficulty was higher in the Az subjects compared with those taking the placebo (P < .01). There was an age relationship with exercise limitation; 4 of the 9 older than 50 years failed to complete the test whereas only 1 of 11 younger than 50 years failed, and there were no failures in the 6 younger than 30 years (P < .05). CONCLUSIONS:In this study group, and despite higher resting Spo2, Az may have compromised exercise at 3459 m altitude during early acclimatization, particularly in older subjects.

Objective.-Ascent to high altitude leads to a reduction in ambient pressure and a subsequent fall in available oxygen. The resulting hypoxia can lead to elevated pulmonary artery (PA) pressure, capillary stress, and an increase in interstitial fluid. This fluid can be assessed on lung ultrasound (LUS) by the presence of B-lines. We undertook a chamber and field study to assess the impact of high-intensity exercise in hypoxia on the development of pulmonary interstitial edema in healthy lowlanders.Methods.-Thirteen volunteers completed a high-intensity intermittent exercise (HIIE) test at sea level, in acute normobaric hypoxia (12% O-2 approximately 4090 m equivalent altitude), and in hypobaric hypoxia during a field study at 4090 m after 6 days of acclimatization. Pulmonary interstitial edema was assessed by the evaluation of LUS B-lines.Results.-After HOE, no increase in B-lines was seen in normoxia, and a small increase was seen in acute normobaric hypoxia (2 +/- 2; P < .05). During the field study at 4090 m, 12 participants (92%) demonstrated 7 +/- 4 B-lines at rest, which increased to 17 +/- 5 immediately after the exercise test (P < .001). An increase was evident in all participants. There was a reciprocal fall in peripheral arterial oxygen saturations (Spo(2)) after exercise from 88% +/- 4% to 80% +/- 8% (P < .01). B-lines and Spo(2) in all participants returned to baseline levels within 4 hours.Conclusions.-HIIE led to an increase in B-lines at altitude after subacute exposure but not during acute exposure at equivalent simulated altitude. This may indicate pulmonary interstitial edema.

Normal cerebral function is dependent upon an adequate and continuous supply of oxygen. This study calculated cerebral blood flow based on assessment of the right middle cerebral artery (MCA) velocity (MCAVel) and MCA diameter (MCADiam) by trans-cranial Doppler and trans-cranial Duplex in normoxia, during acute exposure to 12% normobaric hypoxia for up to 6 hours, and after 3 days exposure to the equivalent altitude, 4392 m, in nine subjects. Mean (SD) MCAVel increased both after 6 hours hypoxia from 76.8 (11.4) to 97.2 (17.4) cms/sec (p<0.001), and after 3 days at altitude from 68.1 (7.5) [sea level] to 76.2 (10.2) [4392 m] (p=0.015). MCADiam increased from 5.07 (0.6) to 6.1 (0.6) mm (p<0.001) after 6 hours of 12% hypoxia. Calculated mean MCA blood flow increased after 6 hours of 12% hypoxia from 5.0 (0.6) mL/sec to 8.9 (1.2) mL/sec, but there was no difference between sea level and 4392 m. Calculated mean cerebral oxygen delivery increased from 72.4 (14.4) to 107 (20.1) mL/sec (p<0.001) after 6 hours of 12% hypoxia and was maintained unchanged at 4392 m. An increase in MCA caliber, rather than blood velocity, was a major contributor to increased oxygen delivery accompanying within the first few hours of exposure to acute hypoxia. During more long-term exposure, increases in MCA velocity and a rise in hemoglobin appeared to be the more important mechanisms in maintaining cerebral oxygen delivery. The implication of this observed change in MCA diameter questions the widely held assumption that MCA velocity is a surrogate for flow during acute hypoxic exposure.

ObjectiveAs inspired oxygen availability falls with ascent to altitude, some individuals develop high‐altitude headache (HAH). We postulated that HAH results when hypoxia‐associated increases in cerebral blood flow occur in the context of restricted venous drainage, and is worsened when cerebral compliance is reduced. We explored this hypothesis in 3 studies.MethodsIn high‐altitude studies, retinal venous distension (RVD) was ophthalmoscopically assessed in 24 subjects (6 female) and sea‐level cranial magnetic resonance imaging was performed in 12 subjects ascending to 5,300m. Correlation of headache burden (summed severity scores [0–4] ≤24 hours from arrival at each altitude) with RVD, and with cerebral/cerebrospinal fluid (CSF)/venous compartment volumes, was sought. In a sea‐level hypoxic study, 11 subjects underwent gadolinium‐enhanced magnetic resonance venography before and during hypoxic challenge (fraction of inspired oxygen = 0.11, 1 hour).ResultsIn the high‐altitude studies, headache burden correlated with both RVD (Spearman rho = 0.55, p = 0.005) and with the degree of narrowing of 1 or both transverse venous sinuses (r = −0.56, p = 0.03). It also related inversely to both the lateral + third ventricle summed volumes (Spearman rho = −0.5, p = 0.05) and pericerebellar CSF volume (r = −0.56, p = 0.03). In the hypoxic study, cerebral and retinal vein engorgement were correlated, and rose as the combined conduit score fell (a measure of venous outflow restriction; r = ‐0.66, p < 0.05 and r = −0.75, p < 0.05, respectively).InterpretationArterial hypoxemia is associated with cerebral and retinal venous distension, whose magnitude correlates with HAH burden. Restriction in cerebral venous outflow is associated with retinal distension and HAH. Limitations in cerebral venous efferent flow may predispose to headache when hypoxia‐related increases in cerebral arterial flow occur. ANN NEUROL 2013;73:381–389

Ataxia at altitude is reviewed in relation to acute mountain sickness (AMS). The cause of ataxia occurring at altitude is unknown but may be hypoxia affecting basal ganglia and hindbrain activity. Ataxia is an important sign of high altitude cerebral edema (HACE) but is less well-established as a clinical feature of AMS. Assessment of ataxia is part of the Environmental Systems and the Lake Louise questionnaires, together with a heel-to-toe measurement. More precise measures of ataxia include the Sharpened Romberg Test (SRT) and the use of unstable platforms. Isolated ataxia at altitude may not be related to AMS or HACE. Age affects ataxia and careful baseline measurements are essential in older subjects before results at high altitude can be interpreted. Testing for ataxia needs to be standardized with sufficient learning time. Ataxia should be distinguished from weakness or fatigue occurring at altitude. Specialized tests have not been shown to be clinically important. Our results above 5000 m showed that an abnormal SRT may be specific for AMS but with relatively poor sensitivity. Wobble board results have not correlated with AMS scores consistently. Other authors using an unstable platform in a chamber and static posturography during 3 days of exposure to 4559 m also found no relationship with AMS scores. Ataxia is a common and important clinical feature of HACE but is unhelpful in the assessment of mild or even moderate AMS in the absence of an altered mental state. The simple heel-to-toe test remains a useful part of the assessment of more severe AMS bordering on HACE.

Hext, Faye, Alison Stubbings, Brynn Bird, Susannah Patey, Alex Wright, and the Birmingham Medical Research Expeditionary Society. Visual analogue scores in assessment of acute mouontain sickness. High AltMed Biol 12: 329-333.- Acute mountain sickness (AMS) is common on ascent to high altitude, with self assessment being the current method used to assess symptoms. The Lake Louise Self-Report Score (LLSRS) and the Environmental Symptoms Questionnaire (ESQ) are widely used and validated. A Visual Analogue Scale (VAS) may be used as a simpler alternative for AMS assessment. Our aims were to compare a VAS using lines of length 100mm, for both individual symptoms of AMS and self-assessed overall AMS with both LLSRS and a shortened Environmental Symptoms Questionnaire (ESQc) on ascent to 4392m. We set out to suggest a specific score as a cut off point for diagnosis of AMS when using the VAS. There were significant positive correlations (p < 0.01), between VAS and both LLSRS and ESQc scores for overall AMS and a composite AMS score derived from the individual symptom scores at 4392m. The sensitivity and specificity of the VAS were calculated as 0.67 and 0.98, respectively, when using the LLSRS as the standard test for comparison, and 0.91 and 0.96, respectively, when using the ESQc for comparison. The cut off point for diagnosis of AMS was calculated to be 22 mm or above when using a VAS for overall AMS or 15 mm or above when using the VAS composite score, when using LLSRS as the comparative test. Our results show significant correlations between the VAS and the LLSRS and ESQc, when assessing AMS at 4392 m. Our study suggests that a VAS could provide a simple alternative method of assessing AMS at high altitude.

OBJECTIVES:Several studies have shown deterioration in colour vision at altitudes above 3,000m. These studies have been conducted in photopic (bright daylight) conditions, whereas many military operations take place in mesopic (dim light) conditions. Data suggests that the tritan colour vision axis (blue cones, TA) are more susceptible to hypoxic insult than protan axis (red cones, PA). The objective of this study was to examine colour vision at high altitude, in mesopic conditions, and using a novel method of assessment to discriminate between the tritan and protan axis. METHODS:We examined 42 eyes (21 subjects, mean age 44, range 22-71), at sea level and within 12-36 hours of exposure to 3300m. This was done in a darkened room, with refractive error correction. Colour vision was studied using ChromaTest, a software programme that analyzes colour contrast threshold (CCT) of both TA and PA. We planned to repeat CCT measurement at 4,392m, but technology failure prevented this. Non-parametric paired data was examined using the Wilcoxon signed rank test. RESULTS:There was found to be no change to either the PA (p = 0.409) or the TA (p = 0.871) upon ascent. Within the PA 16 eyes had a lower CCT at high altitude, whilst 26 were higher. In the TA 20 eyes had a lower CCT and 22 were higher. At sea level, mean CCT for PA was 4.21 (SD 2.29) TA was 7.06 (SD 1.77). At 3,300m mean CCT for PA was 4.36 (SD 2.86) and TA was 6.93 (SD 2.39). CONCLUSIONS:This experiment revealed no changes to colour vision with exposure to 3,300m. This may be below the threshold altitude for cone dysfunction, alternatively colour vision deterioration may be less significant in mesopic conditions.

Acute altitude illnesses are potentially serious conditions that can affect otherwise fit individuals who ascend too rapidly to altitude. They include high altitude headache, acute mountain sickness, high altitude cerebral oedema, and high altitude pulmonary oedema. The number of people travelling to altitude for work (soldiers, miners, construction workers, and astronomers) or for recreation (skiing, trekking, mountain biking, and climbing) is ris­ ing, and increased media attention towards these activi­ ties has also raised the profile of altitude related illness. Typical scenarios in which such illness might occur are a family trek to Everest base camp in Nepal (5360 m), a fund raising climb of Mount Kilimanjaro (5895 m), or a tourist visit to Machu Picchu (2430 m). Awareness of potential altitude related problems is important even for healthcare practitioners working at lower altitude, because patients may ask for advice about the safety of a proposed journey and how to prevent illness at altitude.

Objectives: Systemic arterial pressure rises on acute exposure to high altitude and changes in blood pressure (BP) and endothelial function may be important in the pathogenesis of clinical syndromes occurring at high altitude.Methods: Arterial BP, stiffness (SI) and tone (RI) were studied over 11 days in 17 subjects (three having mild hypertension) ascending to 3,450m and 4,770m using a non-invasive, finger photoplethysmography technique.Results: At 3,450m BP rose from mean 131/75 mmHg (SD 23/12) to 145/86 (23/12) and was maintained at this level (p< 0.001). SI did not change significantly from 8.5 m/sec (2.5) to 9.7 (3.2). RI fell during the first day at 3,450m from 74.4% (7.9) to 70.5% (13.8) (NS p>0.05) and to 69.9% (12.0) (p< 0.02) at 4,770m but then reverted to baseline. Changes in SI and RI did not relate to changes in blood pressure. Changes in both arterial stiffness and tone were similar in those who developed AMS compared with those who did not. Baseline SI tended to be higher in the three subjects with hypertension 11.1m/sec(SD 2.7)) compared with the normotensives 8.3 m/sec (SD 2.7) (NS) and baseline RI lower 74.7% (7.0) compared with the normotensives 76.5% (8.5) (NS). Changes in SI and RI at altitude in the hypertensive subjects were similar to the non-hypertensive subjects.Conclusions: We conclude that acute exposure temporarily affected endothelial function as measured by a change in vascular tone but this did not predict the development of AMS. The rise in arterial BP was not related to changes in arterial stiffness or tone.

Barometric pressure falls with increasing altitude and consequently there is a reduction in the partial pressure of oxygen resulting in a hypoxic challenge to any individual ascending to altitude. A spectrum of high altitude illnesses can occur when the hypoxic stress outstrips the subject's ability to acclimatize. Acute altitude-related problems consist of the common syndrome of acute mountain sickness, which is relatively benign and usually self-limiting, and the rarer, more serious syndromes of high-altitude cerebral edema and high-altitude pulmonary edema. A common feature of acute altitude illness is rapid ascent by otherwise fit individuals to altitudes above 3000 m without sufficient time to acclimatize. The susceptibility of an individual to high-altitude syndromes is variable but generally reproducible. Prevention of altitude-related illness by slow ascent is the best approach, but this is not always practical. The immediate management of serious illness requires oxygen (if available) and descent of more than 300 m as soon as possible. In this article, we describe the setting and clinical features of acute mountain sickness and high-altitude cerebral edema, including an overview of the known pathophysiology, and explain contemporary practices for both prevention and treatment exploring the comprehensive evidence base for the various interventions.

Eur J Clin Invest 2010; 40 (8): 735–741

Metabolic memory and its possible mechanisms are reviewed. In clinical practice in type 1 diabetes the concept of metabolic memory has developed largely from the observations of the Epidemiology of Diabetes Interventions and Complications (EDIC) study, which followed the Diabetes Control and Complications Trial (DCCT). In the former intensive treatment group, after 10 years follow-up, when glycated haemoglobin levels had converged completely, there was less progression of retinopathy and lower rates of proliferative retinopathy. Diabetic nephropathy and neuropathy were similarly reduced. The combined DCCT and EDIC studies showed a reduction in the risk of any cardiovascular disease. Good early metabolic control affects outcome for at least 10 years and it is hoped this information can be translated into clinical practice to reduce significantly the burden of long-term complications.

Gross pupil dynamics are used as an indirect measure of brain function. Changes in hypoxia and intracranial pressure are thought to alter pupil responses to light. This study assessed a portable handheld pupil measuring device (pupillometer) in the field investigating the changes in pupil size, speed of reaction, and rate of constriction/dilatation with hypoxia induced by changes in altitude. A correlation between pupil dynamics and acute mountain sickness was sought. Seventeen volunteers were studied following acute exposure to 3450 m and then during a trek to 4770 m in Ladakh, India. The pupillometer was used to record maximum and minimum pupil diameter in response to a standard light source with calculation of latency, constriction and dilatation velocities. Acute mountain sickness (AMS) was recorded using Lake Louise self completed questionnaires both in the morning and afternoon on each day. Acute altitude exposure resulted in a significant reduction of percentage change in pupil size (36.5% to 24.1% p=<0.001), significant delay in pupillary contraction (latency; 0.208 to 0.223 seconds p=0.015) and a significant slowing of the rate of contraction (constriction velocity; -2.77 mm/s to -1.75 mm/s p=0.012). These changes reverted to normal during a period of acclimatization. A significant diurnal variation in pupil size was also observed. There was no significant difference between subjects with and without AMS. The handheld pupillometer is a suitable robust tool for monitoring changes in pupil dynamics in the field. With acute exposure to hypobaric hypoxia associated with an ascent to a moderate altitude, there is a general slowing of pupil function which reverts to normal within a few days of acclimatization. There appears to be a marked diurnal variation in pupil size. The measurements clearly demonstrated an effect of hypoxia on cerebral function, but these changes did not relate to moderate AMS.