Alveolar PCO2 oscillations and ventilation at sea level and at high altitude.

This study examines the potential for a ventilatory drive, independent of mean PCO2, but depending instead on changes in PCO2 that occur during the respiratory cycle. This responsiveness is referred to here as "dynamic ventilatory sensitivity." The normal, spontaneous, respiratory oscillations in alveolar PCO2 have been modified with inspiratory pulses approximating alveolar PCO2 concentrations, both at sea level and at high altitude (5,000 m, 16,400 ft.). All tests were conducted with subjects exercising on a cycle ergometer at 60 W. The pulses last about half the inspiratory duration and are timed to arrive in the alveoli during early or late inspiration. Differences in ventilation, which then occur in the face of similar end-tidal PCO2 values, are taken to result from dynamic ventilatory sensitivity. Highly significant ventilatory responses (early pulse response greater than late) occurred in hypoxia and normoxia at sea level and after more than 4 days at 5,000 m. The response at high altitude was eliminated by normalizing PO2 and was reduced or eliminated with acetazolamide. No response was present soon after arrival (<4 days) at base camp, 5,000 m, on either of two high-altitude expeditions (BMEME, 1994, and Kanchenjunga, 1998). The largest responses at 5,000 m were obtained in subjects returning from very high altitude (7,100-8,848 m). The present study confirms and extends previous investigations that suggest that alveolar PCO2 oscillations provide a feedback signal for respiratory control, independent of changes in mean PCO2, suggesting that natural PCO2 oscillations drive breathing in exercise.

Serial changes in spirometry during an ascent to 5,300 m in the Nepalese Himalayas.

The aims of the present study were to determine the changes in forced vital capacity (FVC), forced expiratory volume in 1 sec (FEV1) and peak expiratory flow (PEF), during an ascent to 5,300 m in the Nepalese Himalayas, and to correlate the changes with arterial oxygen saturation measured by pulse oximetry (SpO2) and symptoms of acute mountain sickness (AMS). Forty-six subjects were studied twice daily during an ascent from 2,800 m (mean barometric pressure 550.6 mmHg) to 5,300 m (mean barometric pressure 404.3 mmHg) during a period of between 10 and 16 days. Measurements of FVC, FEV1, PEF, SpO2, and AMS were recorded. AMS was assessed using a standardized scoring system. FVC fell with altitude, by a mean of 4% from sea level values [95% confidence intervals (CI) 0.9% to 7.4%] at 2,800 m, and 8.6% (95% CI 5.8 to 11.4%) at 5,300 m. FEV1 did not change with increasing altitude. PEF increased with altitude by a mean of 8.9% (95% CI 2.7 to 15.1%) at 2,800 m, and 16% (95% CI 9 to 23%) at 5,300 m. These changes were not significantly related to SpO2 or AMS scores. These results confirm a progressive fall in FVC and increase in PEF with increasing hypobaric hypoxia while FEV1 remains unchanged. The increase in PEF is less than would be predicted from the change in gas density. The fall in FVC may be due to reduced inspiratory force producing a reduction in total lung capacity; subclinical pulmonary edema; an increase in pulmonary blood volume, or changes in airway closure. The absence of a correlation between the spirometric changes and SpO2 or AMS may simply reflect that these measurements of pulmonary function are not sufficiently sensitive indicators of altitude-related disease. Further studies are required to clarify the effects of hypobaric hypoxia on lung volumes and flows in an attempt to obtain a unifying explanation for these changes.

Elevated plasma cholecystokinin at high altitude: metabolic implications for the anorexia of acute mountain sickness.

The aims of the present study were to measure the satiety neuropeptide cholecystokinin (CCK) in humans at terrestrial high altitude to investigate its possible role in the pathophysiology of anorexia, cachexia, and acute mountain sickness (AMS). Nineteen male mountaineers aged 38 +/- 12 years participated in a 20 +/- 5 day trek to Mt. Kanchenjunga basecamp (BC) located at 5,100 m, where they remained for 7 +/- 5 days. Subjects were examined at rest and during a maximal exercise test at sea-level before/after the expedition (SL1/SL2) and during the BC sojourn. There was a mild increase in Lake Louise AMS score from 1.1 +/- 1.2 points at SL1 to 2.3 +/- 2.3 points by the end of the first day at BC (P < 0.05). A marked increase in resting plasma CCK was observed on the morning of the second day at BC relative to sea-level control values (62.9 +/- 42.2 pmol/L(-1) vs. SL1: 4.3 +/- 8.3 pmol/L(-1), P < 0.05 vs. SL2: 26.5 +/- 25.2 pmol/L(-1), P < 0.05). Maximal exercise increased CCK by 78.5 +/- 24.8 pmol/L(-1), (P < 0.05 vs. resting value) during the SL1 test and increased the plasma concentration of non-esterified fatty acids and glycerol at BC (P < 0.05 vs. SL1/SL2). The CCK response was not different in five subjects who presented with anorexia on Day 2 compared with those with a normal appetite. While there was no relationship between the increase in CCK and AMS score at BC, a more pronounced increase in resting CCK was observed in subjects with AMS (> or =3 points at the end of Day 1 at BC) compared with those without (+98.9 +/- 1.4 pmol/L(-1) vs. +67.6 +/- 37.2 pmol/L(-1), P < 0.05). Caloric intake remained remarkably low during the stay at BC (8.9 +/- 1.4 MJ.d(-1)) despite a progressive decrease in total body mass (-4.5 +/- 2.1 kg after 31 +/- 13 h at BC, P < 0.05 vs. SL1/SL2), which appeared to be due to a selective loss of torso adipose tissue. These findings suggest that the satiogenic effects of CCK may have contributed to the observed caloric deficit and subsequent cachexia at high altitude despite adequate availability of palatable foods. The metabolic implications of elevated CCK in AMS remain to be elucidated.

Hypoxia, hypocapnia and spirometry at altitude.

1. Both hypoxia and hypocapnia can cause broncho-constriction in humans, and this could have a bearing on performance at high altitude or contribute to altitude sickness. We studied the relationship between spirometry, arterial oxygen saturation and end-tidal carbon dioxide (ETCO2) concentration in a group of healthy lowland adults during a stay at high altitude, and then evaluated the response to supplementary oxygen and administration of a beta 2 agonist. 2. We collected spirometric data from 51 members of the 1994 British Mount Everest Medical Expedition at sea level (barometric pressure 101.2-101.6 kPa) and at Mount Everest Base Camp in Nepal (altitude 5300 m, barometric pressure 53-54.7 kPa) using a pocket turbine spirometer. A total of 205 spirometric measurements were made on the 51 subjects during the first 6 days after arrival at Base Camp. Further measurements were made before and after inhalation of oxygen (n = 47) or a beta 2 agonist (n = 39). ETCO2 tensions were measured on the same day as spirometric measurements in 30 of these subjects. 3. In the first 6 days after arrival at 5300 m, lower oxygen saturations were associated with lower forced expiratory volume in 1 s (FEV1; P < 0.02) and forced vital capacity (FVC; P < 0.01), but not with peak expiratory flow (PEF). Administration of supplementary oxygen for 5 min increased oxygen saturation from a mean of 81%-94%, but there was no significant change in FEV1 or FVC, whilst PEF fell by 2.3% [P < 0.001; 95% confidence intervals (CI) -4 to -0.7%]. After salbutamol administration, there was no significant change in PEF, FEV1 or FVC in 35 non-asthmatic subjects. Mean ETCO2 at Everest Base Camp was 26 mmHg, and a low ETCO2 was weakly associated with a larger drop in FVC at altitude compared with sea level (r = 0.38, P < 0.05). There was no correlation between either ETCO2 or oxygen saturation and changes in FEV1 or PEF compared with sea-level values. 4. In this study, in normal subjects who were acclimatized to hypobaric hypoxia at an altitude of 5300 m, we found no evidence of hypoxic broncho-constriction. Individuals did not have lower PEF when they were more hypoxic, and neither PEF nor FEV1 were increased by either supplementary oxygen or salbutamol. FVC fell at altitude, and there was a greater fall in FVC for subjects with lower oxygen saturations and probably lower ETCO2.

Effect of altitude on spirometric parameters and the performance of peak flow meters.

BACKGROUND: Portable peak flow meters are used in clinical practice for measurement of peak expiratory flow (PEF) at many different altitudes throughout the world. Some PEF meters are affected by gas density. This study was undertaken to establish which type of meter is best for use above sea level and to determine changes in spirometric measurements at altitude. METHODS: The variable orifice mini-Wright peak flow meter was compared with the fixed orifice Micro Medical Microplus turbine microspirometer at sea level and at Everest Base Camp (5300 m). Fifty one members of the 1994 British Mount Everest Medical Expedition were studied (age range, 19-55). RESULTS: Mean forced vital capacity (FVC) fell by 5% and PEF rose by 25.5%. However, PEF recorded with the mini-Wright peak flow meter underestimated PEF by 31%, giving readings 6.6% below sea level values. FVC was lowest in the mornings and did not improve significantly with acclimatisation. Lower PEF values were observed on morning readings and were associated with higher acute mountain sickness scores, although the latter may reflect decreased effort in those with acute mountain sickness. There was no change in forced expiratory volume in one second (FEV1) at altitude when measured with the turbine microspirometer. CONCLUSIONS: The cause of the fall in FVC at 5300 m is unknown but may be attributed to changes in lung blood volume, interstitial lung oedema, or early airways closure. Variable orifice peak flow meters grossly underestimate PEF at altitude and fixed orifice devices are therefore preferable where accurate PEF measurements are required above sea level.

High altitude headache: treatment with ibuprofen.

Up to half of those who ascend rapidly to altitudes of over 3,000 m may experience symptoms of acute mountain sickness (AMS) and of these some 95% may suffer from high altitude headache. We report the first controlled trial specifically to assess an oral drug therapy for this common symptom. Subjects were 21 members of mountaineering expeditions to similar altitudes in the Bolivian Andes and the Himalayas in Nepal. The study was of a randomized, placebo-controlled, double-blind, within-patient crossover design. Ibuprofen was significantly superior to placebo both in reducing headache severity and in speed of relief (a mean difference of 94 min in time to no/minimal headache). Only 14% of subjects who initially took ibuprofen felt the need for further medication compared to 83% of those who took placebo first (p = 0.02). Of the 11 subjects completing both phases of the crossover, 8 (73%) favored ibuprofen while the remainder had no preference (p = 0.004). No attributable adverse effects occurred. The results suggest that ibuprofen is a safe and effective treatment for high altitude headache.

Salt and water control at altitude.

The physiological effect of altitude hypoxia, in the absence of exercise, is a sodium and water diuresis with decrease in plasma and extra-cellular volumes. Plasma aldosterone concentrations (PAC) are reduced but plasma atrial natriuretic peptide (ANP) levels are modestly increased. Day-long exercise at low altitude has almost opposite effects on fluid balance. There is an anti-diuresis, sodium retention, expansion of the plasma and extra-cellular compartments, elevation of PAC and ANP. Subjects who develop acute mountain sickness (AMS) show a pathological response to hypoxia even before the development of symptoms. There is an anti-diuresis, sodium retention, increased plasma and extra-cellular volumes and increased PAC compared with subjects resistant to AMS. Plasma ANP tends to be elevated compared with sea level values but the relation of ANP levels to AMS is variable. In general therefore, the pathological response to altitude hypoxia parallels that of exercise at low altitude and is opposite to the physiological response. Both exercise and the pathological response predispose the subject to edema and are probably important in the genesis of AMS.

Effect of captopril on functional, physiological and biochemical outcome criteria in aged heart failure patients.

1. Captopril was evaluated as an adjuvant to diuretic and digoxin therapy in heart failure in old age, using walking ability, minute ventilation and oxygen consumption and plasma atrial natriuretic factor (ANF) concentration as measures of outcome. 2. Twenty patients, mean (s.d.) age 81 (6) years, entered a double-blind, randomised, crossover study of three treatments, a twice daily regimen of captopril (AA), at a dosage established by titration against serum angiotensin converting enzyme (ACE) activity, the same dosage in the morning with placebo at night (AP), and twice daily placebo (PP). Each treatment lasted 3 weeks. A 2 week run-in period on triple therapy, with AA captopril, was used to assess stability and compliance. Seventeen completed all treatments: three completed two. 3. Any benefit of captopril was modest and there was deterioration in gait on the titrated dosage 3 months afterwards (P = 0.04). Efficacy in the old may be greatest when the titrated dose (25 or 50 mg) is given once daily: the multiple daily doses recommended may be unnecessarily demanding. 4. Walking performance was measured by gait analysis (GA) at free walking speed and by a simple walking test (SWT), in which patients stopped at the first relevant symptom. There was a consistent tendency for four measures of performance (GA: speed, stride length and double support time; SWT distance) to be best on the AP treatment, next best on AA, and worst on PP but for the fifth, SWT speed, AP and AA were similar. The trend appeared most marked for SWT distance, mean (s.e. mean) values for AP, AA and PP being 123 (15), 94 (16) and 75 (16) m, respectively. However, the treatment effect did not reach statistical significance at the 0.05 level. 5. There was no significant difference between treatments in minute ventilation, minute oxygen consumption, or their ratio, either at rest or on exercise. 6. Resting ANF concentrations were nearly four times higher (P = 0.0001) in the patients than those, mean (s.e. mean) 66 (5) pmol l-1, in eleven healthy volunteers of mean age 80 (6) years, and the increase on exercise, seen in the controls (P less than 0.01), was absent. In the patients the resting plasma ANF concentration was significantly affected by treatment (P = 0.03), being less on both AP, 245 (9), and AA, 214 (9) than on PP, 264 (10) pmol l-1 (P = 0.02 and 0.03, respectively). 7. Baseline serum ACE activity was induced on active treatment. The change in ACE activity at 3 h post an active dose was significantly greater on AP than AA (P = 0.005). The increased sensitivity to inhibition during once daily administration was reflected in mean arterial pressure. The pre-dose standing pressure was less on AP than on PP (P less than 0.05), and the change in postural fall (pre-dose minus 2 h post), was greater (P = 0.004), but AA and PP were similar in these respects.(ABSTRACT TRUNCATED AT 400 WORDS)

Lymphocyte macrophage interactions: peripolesis of human alveolar macrophages.

Peripolesis is a phenomenon in which a lymphocyte attaches itself to another cell, usually a macrophage or veiled cell, and proceeds to circle around it. In emperipolesis, a related phenomenon, the lymphocyte invaginates the target cell so deeply that it appears to be intracytoplasmic. Lung cells in bronchoalveolar lavage fluids from 20 patients were observed in the living state and filmed. Peripolesis of the alveolar macrophages was recorded in six cases. These patients included one case each of carcinoma of the bronchus, tuberculosis, sarcoidosis and asthma, while two patients had no detectable lung disease. Five out of the six positive cases were females. In every instance there was a high number of lymphocytes in the washing. The peripolesed macrophages were not injured, but temporary alteration of the cell membrane was noted in a minority of film sequences. The peripolesing cells were also examined by transmission and scanning electron microscopy. The lymphocyte was found to be closely attached to the surface of the macrophage, with no invagination and its ultrastructure was that of a small lymphocyte. Peripolesis is probably a physiological mechanism concerned with regulation of the immune response in the lung.

Acute mountain sickness susceptibility, fitness and hypoxic ventilatory response.

In a party of 17 subjects who travelled together to 4,500 m, hypoxic ventilatory response (HVR) and maximum oxygen consumption (VO2max) were measured before departure. HVR was measured under constant and varying alveolar carbon dioxide tension (PACO2) conditions. VO2max was measured by both standard expired gas collection technique on a treadmill and using the "shuttle run" technique. On arrival at altitude, symptoms of acute mountain sickness (AMS) were scored daily for three days. There were no cases of severe AMS but half of the party had mild to moderate degrees of AMS. There was no correlation between AMS scores and HVR by either method of measurement or with VO2max measured by either method of measurement or with VO2max measured by treadmill or shuttle run.

Peak expiratory flow at altitude.

The mini Wright peak flow meter is a useful, portable instrument for field studies but being sensitive to air density will under-read at altitude. True peak expiratory flow will increase at altitude, however, because of the decreased air density, given that dynamic resistance is unchanged. The effect of simulated altitude on peak expiratory flow (PEF) was determined in six subjects with both the mini Wright meter and a volumetric spirometer (which is unaffected by air density). With increasing altitude PEF as measured by the spirometer increased linearly with decreasing pressure, so that at a barometric pressure of 380 mm Hg* (half an atmosphere, corresponding to an altitude of 5455 m) there was a 20% increase over sea level values. The mini Wright flow meter gave readings 6% below sea level values for this altitude--that is, under-reading by 26%. Measurements of PEF made at altitude with the mini Wright meter should be corrected by adding 6.6% per 100 mm Hg drop in barometric pressure.

Atrial natriuretic peptide, altitude and acute mountain sickness.

1. To investigate the mechanisms of acute mountain sickness, 22 subjects travelled to 3100 m by road and the following day walked to 4300 m on Mount Kenya. Control measurements were made over 2 days at 1300 m before ascent and for 2 days after arrival at 4300 m. These included body weight, 24 h urine volume, 24 h sodium and potassium excretion, blood haemoglobin, packed cell volume, and symptom score for acute mountain sickness. In 15 subjects blood samples were taken for assay of plasma aldosterone and atrial natriuretic peptide. 2. Altitude and the exercise in ascent resulted in a marked decrease in 24 h urine volume and sodium excretion. Aldosterone levels were elevated on the first day and atrial natriuretic peptide levels were higher on both altitude days compared with control. 3. Acute mountain sickness symptom scores showed a significant negative correlation with 24 h urinary sodium excretion on the first altitude day. Aldosterone levels tended to be lowest in subjects with low symptom scores and higher sodium excretion. No correlation was found between changes in haemoglobin concentration, packed cell volume, 24 h urine volume or body weight and acute mountain sickness symptom score. 4. Atrial natriuretic peptide levels at low altitude showed a significant inverse correlation with acute mountain sickness symptom scores on ascent.

Respiratory function in the morbidly obese before and after weight loss.

The morbidly obese are known to have impaired respiratory function. A prospective study of the changes in lung volumes, carbon monoxide transfer, and arterial blood gas tensions was undertaken in 29 morbidly obese patients before and after surgery to induce weight loss. Before surgery the predominant abnormality in respiratory function was a reduction in lung volumes. These increased towards normal predicted values after weight loss, with significant increases in functional residual capacity, residual volume, total lung capacity, and expiratory reserve volume. The increases ranged from 14% for total lung capacity to 54% for expiratory reserve volume. After weight loss had been induced the smokers showed mild hyperinflation and air trapping. Resting arterial blood gas tensions improved, with a rise in arterial oxygen tension from 10.63 to 13.02 kPa and a fall in arterial carbon dioxide tension from 5.20 to 4.64 kPa. There was no correlation between weight loss and the changes in blood gas tensions or lung volumes. Loss of weight in the morbidly obese is thus associated with improved lung function. The effects of smoking on lung function could be detected after weight loss, but were masked before treatment by the opposing effects of obesity on residual volume and functional residual capacity.

Hypoxic ventilatory response and acute mountain sickness.

The acute ventilatory response to hypoxia (HVR) and to hypercapnia (CO2VR) was measured in 32 members of two mountaineering expeditions prior to their departure. Both teams made rapid ascents to their base camps at 5200 m and 4300 m and remained there for at least four days. Symptom scores for acute mountain sickness (AMS) were collected daily for these four days. There was a range of AMS from the unaffected to severe sickness requiring evacuation, but there was no correlation between AMS scores and HVR or CO2VR. When ascent to altitude takes a day or more, HVR (measured at sea level) is probably not the major determinant of ventilation and from our studies does not predict susceptibility to AMS. The rate of respiratory acclimatization is probably more important.

Respiratory criteria of fitness for surgery and anaesthesia.

A retrospective analysis has been undertaken of 53 operations in 42 patients with severe chronic obstructive airway disease. All patients had a forced expiratory volume in 1 second between 0.3 and 1 litre, but the outcome of surgery was successful after their first operations, all of which were elective; 38 of the 42 had uneventful anaesthesia and surgery together with a normal postoperative period, while four had artificial ventilation of the lungs. The best predictors of the use of postoperative ventilation were the arterial PO2 and whether the patient was dyspnoeic at rest.