D1. Altitude- experiments Flashcards
Summary
AMS
HAPE
HACE
CMS
- Groves 1985
Hypobaric chamber 40 days gradual increases in hypobaria up to Mt Everest
Pulmonary artery catheterization
Increase in mPAP and PVR with altitude increased further by exercise
Breathing 100% oxygen didn’t reverse this suggesting remodelling
Controlled environment not similar to high altitude
- Forster 1975
Electrode measurements to assess arterial blood and CSF acid-base status in 7 healthy men at 250m and 4300m
Ventilatory acclimatisation accompanied by reductions in [HCO3-] of -5 to -7 meq/L in blood and CSF
Compensation of pH incomplete (70-75%), CSF remained alkaline
May suggest ventilatory acclimatisation is not triggered by acid-base changes
Assumed lumbar spinal fluid acid-base changes mirror CSF, which may not be true
- Hodson 2015
Plethysmography to measure tidal volume and respiratory rate in hypoxia
Used PHD/HIF-1alpha/HIF-2alpha knockout mice with Cre recombinase
PHD2 inactivation enhanced hypoxic ventilatory responses
HIF-2alpha inactivation impaired ventilatory acclimatisation and carotid body proliferation
PHD2/HIF-2alpha essential in modulating ventilatory sensitivity via carotid bodies
Murine models may not translate due to species differences
- Groves 1993
Tibetans studied at 3600m using catheterization
PAP similar to sea level, no increase with hypoxia or exercise
Small sample size, no Han Chinese control
- Yi 2010
Sequenced 50 Tibetan exomes vs Han Chinese and Danish
EPAS1 identified as top gene for selection
EPAS1 correlated with erythrocyte count
Intronic SNP in EPAS1 found in 87% Tibetans vs Han
- Bert 1878
Pressure chamber altered PO2 and barometric pressure independently
Both bird and Bert lost consciousness at same PO2 regardless of pressure
- Karinen 2010
Measured resting and exercise SpO2 in 83 people ascending
AMS score tracked with Lake Louise scoring
Lower SpO2 during exercise in those with AMS
Contradicted by Chen 2012 who found 1% drop predictive of AMS
- Sagoo 2017
Serial MRIs in 12 exposed to normobaric hypoxia 22 hours
Little vasogenic or cytotoxic oedema
Sleep increased brain parenchymal volume
HACE and AMS may differ in mechanism
Normobaric model used
- Severinghaus 1966
Used N2O tracer and arterial/jugular samples to assess CBF
25% increase in cerebral blood flow at 3810m
Could affect NO metabolism
Could have used radioactive xenon
- Bauer 2010
Mice exposed to 8% oxygen
Some treated with MMP inhibitors
Immuno for Zo-1 showed disrupted tight junctions in untreated
MMP9 implicated via gelatin zymography
- Hackett 1998
MRI of 9 patients with HACE >5000m
White matter vasogenic oedema, esp. corpus callosum
2/9 had no MRI abnormalities (skiers)
- Wang et al 2018
Rats exposed to hypobaric hypoxia vs controls
AQP4 upregulated in cortex via WB and RT-PCR
Dexamethasone and puerarin reduced AQP4 and improved cognitive test
Did not test sufficiency of AQP4 changes to induce/prevent HACE
- Kallenberg 2008
MRI showed haemosiderin in HACE vs AMS
T2 scans weeks after HACE
Microbleeds confirmed to persist in Hackett 2019
- Fischer 2001
Porcine endothelial monolayers in normoxia/hypoxia
Measured permeability via radioactive inulin transfer
Dexamethasone reduced VEGF and permeability
Model limits in vivo translation
- Euler & Liljestrand 1946
Demonstrated hypoxic pulmonary vasoconstriction in awake cats
Pulmonary pressure increased in hypoxia, decreased in high O2
Tried to rule out nervous/adrenal factors
Could have done vagotomy/adrenalectomy to confirm
- Droma 2002
Japanese climbers, venous DNA samples
eNOS Glu298Asp polymorphism linked to HAPE susceptibility
Not confirmed in other ethnic groups
- Sartori 1999
32 mountaineers to 4500m Capanna Regina
PAP by Doppler echo, ET-1 by radioimmunoassay
PAP correlated with ET-1
ET-1 not truly a hormone
- Operation Everest II 1980s
Volunteers in altitude chamber simulating Everest
Exercise raised pulmonary artery pressure
Chamber model slow ascent, not real-world HAPE trigger
- Maggiorini 2001
48-hour ascents to high-altitude lab
PAP decay curves by Doppler
HAPE-susceptible had higher PAP
19mmHg threshold predictive of oedema
- Hlastala 2004
Injected microspheres into pig lungs
Breathing hypoxic air
Metaclustering linked lung zones to resistance
3D flow maps created
- West 1995
Rats in hypoxic chamber 48 hours
Lung electron microscopy
Endothelial disruption and barrier rupture
Cause unclear: pressure vs hypoxia
- Swenson 2002
16 non-acclimatised, 10 HAPE susceptible to 4500m
Bronchoalveolar lavage for immune cells, cytokines
No significant inflammation difference
Other studies focus on late-stage HAPE
- Bärtsch 1991
Capanna Regina ascent >4500m
Radiographic oedema and PAP by Doppler daily
Nifedipine reduced oedema and PAP
Doppler PAP 48% overestimated vs RHC
- Hafezi-Moghadam 2002
HUVECs treated with dexamethasone
eNOS assay using radioactive arginine/citrulline
eNOS up in 10 minutes suggests PI3K, not genomic
HUVEC model limited
- Smith & Talbot 2009
Unacclimatised to Cerro de Pasco (~4400m in 8h)
PAP by Doppler before/after iron sucrose
PAP increase reversed after 3 days altitude
- Grocott 2009
ABGs during ascent/descent
PO2 dropped but Hb rose
ABGs stable due to acclimatisation
- Liu 2020
Bone marrow erythroblasts from 21 CMS vs 14 controls
EPAS1 expression via RT-PCR, WB
Higher EPAS1 linked to RBC count
Overexpression sped up proliferation
Cancer cell line used
- Butscher 2008
Systematic review
O2 saturation after 30min simulated ascent >2500m predicted AMS
Suggested sympathetic activation signs may also predict
