Assuming you have access to all facilities and measuring devices you wish for, how would the ideal screening protocol for AMS susceptibility (theoretically) look like?
Since we are talking about a screening procedure, let’s limit the maximum time of the test procedure to ~2 hours (excluding analysis of the data). Let’s also not account for the burden of the test procedure on the subject. Hence if you would like to take arterial blood samples, biopsies or perform any other invasive measurements to increase the accuracy of the prediction, go for it! Finally, let’s assume that medical pathologies potentially influencing AMS development have already been excluded and our subjects are not taking any medication or supplements.
Let me give a head start for possible elements that should/could be included in the screening procedure:
1. Anamnesis:
Previous exposure to altitude and history of AMS (Schneider et al., MSSE, 2002).
+ modifiable factors such as ascent profile, sleeping altitudes, exertion at altitude, financial costs/interests, alcohol use at altitude, … .
2. Determination of genetic profile:
Specific interest in ACE, AGT, GNB3, GSTM1, GSTT1, HSP70A1B, HSP70A1L and NOS3 (review by MacInnis et al., J Occup Environ Med, 2011) + EGNL1 (Zhang et al., Int J Mol Sci, 2014) and VEGF (Ding et al., J Int Med Res, 2012)
3. Test procedure:
Example: 30 min rest in normoxia followed by 30 min rest in hypoxia (hypobaric chamber set at ~4000 – 4500 m?) + incremental exercise test to exhaustion in hypoxia.
Measurements during test procedure:
a) Hypoxic ventilatory response (HVR): [delta Ve/delta Spo2] after 30 min rest (so after the hypoxic ventilatory decline). Delta breathing frequency.
b) Hypoxic cardiac response (HCR): [delta HR/delta SpO2] after 30 min rest.
c) Capillary blood sample to measure Hb concentration with radiometer
--> Formula by Savourey et al., EJAP 2007: AMSmean = 3.91 + 0.059 x delta breathing frequency + 0.438 x HCR – 0.135 x CpO2 (CPO2 = [Hb] x SpO2 x 1.34). AMSmax = 9.47 + 0.104 x PetO2 - 0.68 x CpO2
d) SpO2 at rest, at submaximal intensities, at maximal intensity (Seys et al., Thorax, 2013) and after 20 min of recovery (Burtscher et al., Sleep Breath, 2008).
e) Aerobic exercise capacity: is the expected exercise intensity during mountain climbing (gain of ~300 m in altitude/hour, corresponding to 1.5 W/kg on the cycle ergometer or 2.4 km/h on treadmill with inclination set at 15%) below the anaerobic threshold? Estimation by spirometry and capillary lactate concentrations at the end of each step of the incremental exercise test. (See review Burtscher, Wien Klin Wochenschr, 2004)
f) Arterial adrenaline concentration: [delta arterial adrenaline concentration after 30 min rest in Hyp vs 30 min rest in Nor]. (Kamimori et al. Aviat Space Environ Med, 2009)
g) Heart rate variability: should we use paced or spontaneous breathing when assessing HRV at altitude? Specific attention to RMSSD (Karinen et al., HABM, 2012) and LF:HF ratio (Loeppky et al., HAMB, 2003 and Huang et al., Clin J Sport Med, 2010)
h) Low exhaled nitric oxide (FeNO) at rest, in normoxia, predicts AMS (MacInnis et al., Respir Physiol Neurobiol, 2012 and You et al., Wilderness Environ Med, 2012)
i) Could exercise induced hypoxemia at sea-level and flow-limitation be related to AMS development? (Chapman, BJSM, 2013).
j) What about muscle and cerebral oxygenation (NIRS)?
k) What about cerebral perfusion and edema (MRI)? Apparently not that useful, since cerebral edema seems to be related to hypoxic exposure but not specifically to AMS (Mairer et al., PLoSONE, 2012)?
What else should be considered to be included in the screening procedure? Happy to hear your comments!
Cheers,
Stefan
Dear Stefan,
You have very nicely compiled all the reported procedures for AMS screening. But the first major challenge is experimental setup and the number of subjects. To me, these are the critical parameters for screening AMS.
If you are screening for AMS in a laborotary setup, then the size/ volume of hypoxia chamber along with instruments and technical staff is a major constraint (keeping in mind that you have limitations of opening the door of the chamber).
Secondly, the number of subjects is another constraint. Given the number of parameters and techniques you have mentioned above, I like my subjects to come after 12 h of fasting for the test. This gives me more flexibility for biochemical and hematological analysis. But how many number of samples you can handle in the morning (in the hypoxia chamber) with the above mentioned recordings. (Please keep in mind that hormonal patterns also play a major role in hypoxia response).
My personal experience says, if a subject is AMS susceptible that does not mean that with every exposure he or she will develop AMS symptoms.
Moreover, you can neither put a MRI machine in hypoxia chamber or field conditions !!!!!!!!
It is a tough challenge.
So, I use a combination of techniques (1) SpO2 levels, (2) LLS scoring, (3) exhaled NO, (4) Plasma NO metabolites, (4) HRV and (5) Echo.
Believe me, with all these I still fine problems in predicting AMS.
Cheers,
Niroj
Hello,
HVR is definitely the traditional way to assess susceptibility.
Pr. JP Richalet proposed an alternative test including an exercise component and poikilocapnic hypoxia. His argument is that one rarely remains seated in the field and altitude is poikilocapnic.
His test involves 5min at rest in normoxia (Nx), 5min at rest in hypoxia (4800m equivalent or 11.5%), 5min of exercise at a moderate intensity (about 30% of VO2max in normoxia or 130bpm), 5min of exercise in Nx at the same intensity.
Brugniaux et al. Eur J Appl Physiol, 2006.
Our group recently suggested that subtle alteration in dynamic cerebral autoregulation could also be used to predict susceptibility to AMS.
Cochand et al. Stroke, 2011.
Best
Julien
Dear Niroj,
Thank you for your response!
Agreed. It’s not because a subject developed AMS once that he will develop AMS on future exposure to altitude; nice paper from MacInnis about this subject (MacInnis et al., Wilderness & Environmental Medicine 2014). Nevertheless, a history of AMS remains one of the best predictors for future development of AMS (Schneider et al., MSSE, 2002).
Do plasma NO metabolites hold predictive value for AMS? And what do you use the Echo for?
All the best and thank you for your contribution,
Stefan
Dear Julien,
Interesting, sea-level cerebral autoregulation as a risk factor for AMS (and HACE). Individuals less capable of buffering rapid surges in mean arterial pressure more vulnerable to vasogenic edematous brain swelling and intracranial hypertension at high altitude (Cochand et al. Stroke, 2011).
Thanks for your input!
Stefan
I find the whole NO topic an absolute minefield...
We have no agreement between the exhaled and the blood-borne (measured using OBC) be it in normoxia before/after exercise or after 6h of passive exposure to hypoxia (12%, circa 4500m).
Therefore, I/we would tend to be cautious when interpreting results from exhaled NO.
We haven't published that yet, only presented these results at the Physiological Society main meting in 2011 (exercise) and 2012 (hypoxia).
Julien
Adding to the topic of NO: our group (Masschelein et al., JAP, 2012) reported increased SpO2 and muscle oxygenation with dietary nitrate supplementation (and hence increased plasma nitrate and nitrite) in hypoxia. However, nitrate supplementation did not attenuate the hypoxia-induced drop in cerebral oxygenation (measured by NIRS at the frontal cortex) or symptoms of AMS. FeNO was not measured in this study.
Dear Stefan:
Interesting and highly complex question. I enjoyed your summary of possible tests. I work in high altitude medicine in the city of La Paz, Bolivia (3510m) at our Institute which is 45 years old. The first high altitude clinic in the world. This has given us over all these years, a very rich experience caring for patients with AMS. Some of our papers are at ResearchGate. We have a different focus of hypoxia with respect to sea level physicians and physiologists. We organized the First World Congress on High Altitude Medicine and Physiology here in La Paz, back in 1994. We presented a case of a patient with a PaO2 of 20 mmHg. Nobody believed us. They thought it was a systematic error. Well over the years this has been confirmed on several occasions.
What is the relation to your question? Well the complexity of AMS. It is truly multi-factorial and with poorly described or poorly understood biological responses to hypoxia. There are endless possibilities: the presence of inter-current viral infections, the hypoxic stress individual response, underlying disease, abnormalities in pulmonary vessels, hypertensive response to hypobaric hypoxia, multiple different types of anemia, possible hemoglobin variations, red cell wall immune characteristics, etc, etc. it goes on in an endless chain of suggestions. Unfortunately, we have not published many observations, due to no support at all. But we invite you to read some of our papers, to get a glimpse of our different points of view.
Bottom line concept: there is not one test to define who will have AMS. I doubt there ever will be. Many tests can be performed, but these will miss out many many possibilities. Medicine is an art, and in spite of all the technology, continues to be an art!
Best regards,
Dear Gustavo,
Thank you for sharing your view and expertise!
It was with great interest that I read your paper 'Tolerance to hypoxia', in which a formula is proposed to quantify tolerance to hypoxia [Hb/PaCO2*3.01] and (ABG-) data from an enormous data base is reported.
Difficult for me to understand the limited support or interest from the scientific community in the data obtained at your institute, which obviously could contribute to better understanding in the mechanism of AMS and acclimatization to hypoxia.
I realize that the pathology of AMS is complex, and that we are still a long way from reasonably sensitive and specific AMS-susceptibility screening procedures. But don't think this will hold us down trying to unravel this interesting pathology ;-)
All the best,
Stefan