Professor Jo Bradwell, one of the founding members of the Birmingham Medical Research Expeditionary Society (BMRES), has recently written a fascinating book about the group's many adventures. Further details can be found here. Jo has very kindly allowed us to reproduce a series of extracts. Here's the first and reveals the surprises that research can bring...
The 35th reunion of BMRES in Birmingham on 13 October 2012 was attended by over 50 members. We became rather jolly – old friends, ancient stories, re-lived heroics and happy memories. However, it had been six months since the Bhutan expedition and we were itching for a quick fix, an expedition to satisfy the mountain rat. Rather than wait two years for a big expedition, why not go back to Testa Grigia for a mini-trip? There was also unfinished business. Mark and Yash had shown that there was evidence of early pulmonary oedema on ultrasound lung scans "comet tails" following hard exercise at 4,000 m. Since acetazolamide reduced mountain sickness, perhaps it would also reduce lung comets? Together we hatched a study of exercise and acetazolamide. I announced the possibility of a trip at the end of the meeting, when minds were chirpy and the glow of old successes was in the air. Immediately, Pete Forster put up his arm in support, followed by numerous others. The game was on.
We proposed a double-blind trial of acetazolamide versus placebo using a standardised exercise test on the redoubtable Alticycle, intense enough, we hoped, to provoke lung comets. The bike had failed us in Bhutan for want of a good service, but Steve Harris, who had designed and built the bike, agreed to give it a thorough overhaul. Over the next few weeks, the details of the trial were agreed so we booked the Lombard Hut for 20 people for early April.
The exercise intensity had to be sufficiently long and hard to produce lung comets but not too hard that some failed to finish the test. Using a hypobaric chamber, Kimberly Ashdown (Steve Myers’s PhD student) showed that a workload of 60% sea-level peak power for 15 minutes, at the equivalent altitude of Testa Grigia (3,459 m), was about right. The next step was to determine sea-level peak power. Because of a busy schedule, Steve Myers didn’t release the bike until a month before departure, and it still wasn’t functional. Steve Harris had to work frantically to get it ready in time for a weekend of baseline studies at his house in Farnham shortly before departure. I hated those last-minute problems, which dogged us from time-to-time. A second weekend of baseline studies was planned for Birmingham but we had the worst March snowstorm in Britain for years and the lowest March temperatures since records began. Rail services were massively disrupted, while parts of Yorkshire were cut off. Birmingham had ten inches of fresh snow. I could feel a disaster looming, since individuals had to come from as far north as Cumbria. Remarkably, after a series of phone calls and changed schedules, everyone managed to make it and we established everyone’s peak power.
Home from home!
We hired two minivans, fixed up a Channel Tunnel crossing for 10 pm on Friday 5th April and off we went, collecting various participants on the way. By midday on Saturday, having driven overnight, we were in Cervinia, in good weather and ready for the mountain ascent. Euros handed out to willing hands helped move bags and equipment through the three lift systems to Testa Grigia, where we arrived at 4 pm to a warm welcome from the hut guardian. However, it is not a salubrious establishment. On this occasion, the showers were frozen and toilets only semi-functional, but there was cold running water and a helpful supply of red wine. The bunks, in crammed rooms, were rickety, with saggy boards and dubious cleanliness, but at least we were warm.
We cleared one bunkroom for experiments while another became the ‘aviary’ – the girls’ room. It smelt rather better than the men’s bunkrooms. We went to bed happy after a jolly evening. The tests were planned for 7 am sharp next morning. In research, results usually reveal themselves as planned, hypotheses are confirmed. Maybe not enough data, perhaps some technical failures or over-hyped outcomes, but rarely opposite to expectations. All our thoughts and prejudices had assumed that subjects on acetazolamide would perform better than those on placebo – but that was not what happened.
Participants were exercised in matched pairs of drug or placebo based upon fitness and hours since ascending the previous afternoon. Since the trial was double-blinded, those managing the Alticycle, Steve, Nick, Susie and myself, did not know individuals’ medications. The first person, Angie Miller, managed the 15 minutes of hard exercise reasonably well. Perfect, we though, since it meant the exercise intensity was about right. Next up was Angie’s husband Alastair. However, within a couple of minutes he was struggling – puffing, grunting and gasping with the effort. I looked on anxiously wondering if something was wrong with the bike settings, or perhaps with his heart or lungs. It was unlikely to be a medical problem as he was a strong cyclist, but by three minutes he was overwhelmed by the effort and had to stop. As his gasping slowed and his grim facial expression settled, he complained that the exercise was far too hard and he could not possibly have continued. After five minutes rest, we re-started him at 30% less workload, still hoping it would be enough to produce lung comets.
As he had failed the test, I presumed he was on placebo. Many years earlier, we had showed that acetazolamide improved exercise performance. Maggie, our doctor to the group, thought he might be on acetazolamide since he had complained of tingling (a common side effect). I didn’t believe her. People on acetazolamide had higher oxygen saturations at rest – surely that translated into improved exercise performance?
The Alticycle in action!
The third subject completed the exercise test but the fourth failed. He was young – 31, considerably younger than Alastair (54) – so most unlikely to have a heart problem. Again, Maggie thought he was on acetazolamide. We ploughed on with testing everyone. My turn came. I could tell from lack of tingling that I was on placebo. How was I going to perform? I lay down on the bike, my feet strapped to the pedals, pulse oximeter attached and started. After a few minutes, I was gasping and puffing but the effort was sustainable. By five minutes I felt that I would complete the test; it was very hard but just sustainable. The countdown to 15 minutes was shouted out with each turn of the pedals. My legs ached, my chest ached, I was dizzy with the effort but made it.
In total, five failed to finish, their oxygen saturations plummeting at high exercise intensities. Because of the double-blind nature of the study we didn’t know the drug allocation, but if our suppositions were correct, we had a problem. How could individuals on placebo possibly perform better than those on acetazolamide? Had we mixed up the capsules? Had the baseline tests been inaccurate? Had we paired the individuals wrongly? Full analysis would have to wait until we looked carefully at the results and broke the code – which, following our agreed protocol, was when we got home.
Apart from another day of exercise tests, we had four days skiing in front of us, which, of course, was largely why we were in the Alps. There had to be a strong lure to entice 21 people to leave their families, partners, jobs and home comforts for a week in a high hut to sleep in bunk beds crammed into tiny rooms. The research and experiments may be the bricks of the BMRES structure, but the high mountains with their skiing and climbing were the fire escapes from high pressure jobs in hospitals.
The second day of exercise tests never happened. While the snow was good early in the week, the weather was rather poor. As the day dawned for the second set of tests three days later, it was bright sun with 30 cm of fresh powder. We made all the excuses possible under the clear skies to avoid repeating the tests. Each person’s daily exercise had been different and four people had left early because of prior commitments. A total of 20 people was close to the minimum required for useful statistical rigour – and we were now down to 17. All willpower for work evaporated. I was itching to discover who was on which pill and whether acetazolamide had really affected exercise. We argued about breaking the code, eventually reaching a compromise. I would forgo a day of skiing to analyse the data and, in the evening, we would reveal the results. Over dinner, Maggie revealed each person’s medication, one by one, comparing it with their exercise tests. The results were remarkable: acetazolamide had reduced exercise performance, not enhanced it. It was a huge surprise – no one would have taken a bet on that. Breaking the code was one of those many memorable days on BMRES adventures; in this case, we found results that were the exact opposite of what we had expected. Acetazolamide was not as benign as we had always supposed. We celebrated with a jeroboam of Barbaresco.
Saturday, our departure day, arrived all too quickly. Highly organised, we shuffled our kit down the lift system then rescued the two vans from under the large snow fall for the race home. The vehicles may have been limited to 100 kph, but there were other important factors that determined who arrived back first. Ian got lost twice and ran out of diesel approaching Birmingham (which he grudgingly admitted after much cross-examination). Our van beat the competition by four hours.
Bradwell AR, Myers SD, Beazley M, Ashdown K, Harris NG, Bradwell SB, Goodhart J, Imray CH, Wimalasena Y, Edsell ME, Pattinson K, Wright AD, Harris SJ, and Birmingham Medical Research Expeditionary Society.
Exercise limitation of acetazolamide at high altitude (3,459 m). Wilderness and Environmental Medicine. 2014;25(3):272-277.
The study can be found here.
The Birmingham Medical Research Expeditionary Society (BMRES) and the British Mountain Medicine Society (BMMS) have joined forces to organise the 2021 Altitude Research Conference. The face-to-face event will take place in Birmingham on the 11th September. Speakers will include Peter Bartsch, Jo Bradwell and Chris Imray. There will also be presentations from members of the UK's leading research groups as well as ample opportunity for researchers, young and old, to present posters and short talks about their work.
Further details can be found here.