Altitude Medicine updates and controversies

1
Altitude Medicine updates and controversies

• Corinne Michèle Hohl R3
• Royal College Emergency
• Medicine Training Program

2

• Millions of visitors per year to high altitude
• destinations world wide, increasing trends
• gt20000 British trekkers to Nepal annually
• 90000 nights spent in huts gt 2500m in
  Switzerland/yr
• Ski industry.
• Aviation industry.
• Pathophysiologic modelling of hypoxic processes
  in health indivisuals.
• Military operations.

Thorung La Pass, 5467m
3

• Physics

Himalayan Peaks over Kathmandu, Nepal
4
Physics

• Hypobaric hypoxia
• Alveolar gas equation
• PAO2 (PB-PH2O) FiO2 - PaCO2 /R
  (0.003PaO2)
• PAO2 varies proportionally to PB, as it declines
  PaO2declines.

Himalayan Peaks over Kathmandu, Nepal
5
Physics

• Further from the earths surface gravitational
  pull diminishes affecting gas density, pressure
  and volume.
• Hypobaria PB PiO2 O2 sat
• Sealevel 760mmHg 160mmHg 100
• 1829m 608mmHg (80) 128mmHg 94
• 5486m 380mmHg (50) 80mmHg 78
• 8848m 240mmHg (31) 43mmHg 56
• .

Himalayan Peaks over Kathmandu, Nepal
6
Adaptive mechanisms

• As PaO2 declines to 60mmHg chemosensors in the
  carotid body trigger an increase in minute
  ventilation
• Hypoxic Ventilatory vesponse (HVR)
• PCO2 drops --gt resp alkalosis --gt limits HVR.
• Low HVR at SL predicts increased susceptibility.
• (Krieger Holz, 1999, Fagan Weil, 2001)

Himalayan Peaks over Kathmandu, Nepal
7
Adaptive mechanisms

• 24-48h bicarbonate diuresis --gt compensatory
  metabolic acidosis --gt minute ventilation
  increases.
• Catecholmine release --gt increase in HR and PAP.
  Acclimatization correlates with return of resting
  HR to baseline except at extreme altitude.
• Increase in cerebral blood flow offset by the
  vaso-constrictive effect of hypocapnea.
• 4-5days hematopeisis after 4-5 days. (Lundby et
  al. 2001)

Himalayan Peaks over Kathmandu, Nepal
8
AMSAcuteMountainSickness
Trekkers on the Annapurna Circuit
9
AMSEpidemiology

• Maggiorini et al. 1990 visitors to Swiss
  mountain huts 34
• 2850-3050m 9-13
• 3650m 34
• 4559m 52 (11 with HAPE or HACE)
• Houston. 1985 and Hackett et al. 2001 Colorado
  skiers
• 1850-2800m 12 - 22
• Montgomery et al. 1989 Rocky Mountains
• 2000m 25
• Hackett et al. 1976 Trekkers in Nepal
• 4200m 43-52 AMS

Trekkers on the Annapurna Circuit
10
AMS - Pathophysiology
11
AMS Pathophysiologycerebral autoregulation
12
AMS Pathophysiology cerebral autoregulation
Jansen et al. Cerebral Autoregulation in Subjects
Adapted and Not Adapted to High Altitude. Stroke
2000. Methods 10 subjects at SL 9 sherpas 10
newcomers at 4243m w/o AMS. Phenylephrine
infusion to increase MABP (20-30mmHg) and
challenge CA. Measured Vmca (MCA blood flow) by
transcranial doppler as a measure of
CA. Results SL No change in Vmca after
phenylephrine in any group --gt intact CA. 4243m
In both sherpas and newcomers increase in MABP
triggered an increase in Vmca at altitude (124
in sherpas vs. 111 in newcomers -
NS). Conclusion Both sherpas and newcomers w/o
AMS have impaired CA at altitude. Is AMS a
reflection of an individuals adaptability to
impaired CA?
13
AMS - Signs Symptoms

• Lake Louise Consensus 1993
• Headache in an unacclimatized individual who
  recently arrived at gt 2500m plus one or more
• n/v, anorexia, insomnia, dizziness or fatigue.
• 1-10h after ascent, remits in 4-8days.
• No diagnostic physical findings except low O2sat.
• (Hackett Roach, 2001, Forwand et al. 1968)

Machhapuchhre, 6993m
14
AMS - Signs Symptoms

• Risk factors
• Prior history
• Residence below 900m
• Exertion
• Preexisting cardiopulmonary disorders
• Younger individuals (lt50)
• Men more susceptible to HAPE but not AMS
• Dehydration
• (Hackett Roach, 2001, Basnyat, 1999)

Machhapuchhre, 6993m
15
AMS - Signs Symptoms

• Fitness is NOT protective
• Roach et al. 2000
• Cross-over design, n7, exposed to simulated
  alt.(4800m) x10h.
• Symptom scores of AMS 4.4 ( 1.0) with exercise
  (50 max workload) vs. 1.3 ( 0.4) when
  sedentary.
• Normoxic controls who exercised had no symptoms
  of AMS.
• Sa O2 during exercise 76 vs 81.
• C Does exercise-induced exaggeration of
  hypoxemia worsen AMS?
• (Roach et al, 2000 Hackett Roach, 2001)

Machhapuchhre, 6993m
16
AMS - Signs Symptoms

• Is there a way to predict individual
  susceptibility?
• Prior history of AMS/HAPE is most reliable.
• Low HVR too much overlap with the range of
  normal.
• High PAP with exposure to hypoxia or exercise
  poor sensitivity and specificity.
• Avoid by prevention and ascent rates to lt
  300m/day above 2000m in first exposure to
  altitude or susceptible individuals.
• (Bärtsch P et al. 2001)

Machhapuchhre, 6993m
17
AMS - DDx

• acute psychosis hangover seizures
• AV malformation hypoglycemia stroke
• brain tumor hyponatremia TIA
• CO poisoning hypothermia viral infection
• CNS infection drugs bact. infection
• Dehydration EtOH exhaustion
• DKA migraine
• (Hackett Roach, 2001)

Machhapuchhre, 6993m
18
AMS Prevention

• Graded Ascent
• Prior hypoxic exposure
• Oxygen
• Acetazolamide
• Dexamethasone
• Nifedipine
• Antioxidants

Bhulebhule, 840m
19
AMS - Prevention normobaric hypoxia

• Burse et al. Acute Mountain Sickness at 4500m Is
  Not Altered by Repeated Eight-Hour Exposures to
  3200-3550m Normobaric Hypoxic Equivalent. Aviat
  Space Environ Med 1988.
• Methods
• Single-blinded design. Exposed 10 soldiers to
  normobaric hypoxia (FiO2 12, 3960m equivalent)
  and 10 soldiers to SL conditions (FiO2 21)
  with a portable altitude simulator for 8h/day for
  10 d prior simulated ascent.
• Results
• Trend towards higher PetO2 and lower PCO2 in
  experimental group (NS).
• Trend towards lower symptom scores in exp grp
  (1.0 0.4 vs 1.6 0.4).
• Conclusion
• No ventilatory advantage.
• There may be a marginal benefit of
  acclimatization with respect toAMS scores.
• A benefit of longer or more intense program
  cannot be ruled out.

Bhulebhule, 840m
20
AMS - Prevention Acetazolamide

• Forwand et al. Effect of Acetazolamide on Acute
  Mountain Sickness. NEJM 1968.
• Hypothesis
• Studies in the 30s showed improvement of AMS
  symptoms and respiratory alkalosis with CO2
  inhalation.
• Acetazolamide inhibits renal carbonic anhydrase
  and increases bicarbonate excretion resulting in
  metabolic acidosis.
• Methods
• RCT, n 43 male soldiers.
• Acetazolamide 250mg q8h vs. placebo 32h prior
  ascent to 12800 ft, continued for 40h.
• Results
• Tx group lower serum HCO3-, lower blood pCO2,
  higher minute ventilation, and no significant
  change in blood pH from SL.
• HCO3- in tx and placebo group approximated on
  days 4 and 5.

Bhulebhule, 840m
21
AMS - Prevention Acetazolamide
Acetazolamide
HCO3
Blood pCO2
Acetazolamide
pH
Acetazolamide
Bhulebhule, 840m
22
AMS - Prevention Acetazolamide

• Forwand et al. 1968.
• Headache, gastrointestinal symptoms and insomnia
  significantly reduced in Acetazolamide group.
• Correlation of AMS symptoms with pCO2 levels
• high pCO2 levels correlated with greater AMS
  symptoms.
• Remission of AMS in both treatment and control
  levels correlated with decrease in serum pCO2.
• Conclusions
• Acetazolamide 250mg q8h reduces symptoms of AMS,
  and reduces metabolic derangements at altitude.
• No side effects reported.

Bhulebhule, 840m
23
AMS - Prevention Dexamethasone

• Johnson et al. Prevention of Acute Mountain
  Sickness by Dexamethasone. NEJM 1984.
• Hypothesis
• If AMS is caused by vasogenic cerebral edema
  dexamethasone should be effective.
• Methods
• RTC, double-blind, cross-over.
• n12 4 did not complete crossover.
• Simulated altitude (4570m) for 42h in
  decompression chamber.
• Dexamethasone 4mg q6h vs placebo starting day
  prior to decompression until recompression.
• Symptom evaluation 5 times during decompression.

Tal, 1680m
24
AMS - Prevention Dexamethasone

• Johnson et al. 1984.
• Results Placebo Dexanethasone
• AMS - C 1.09 0.18 0.26 0.08 plt 0.05
• AMS -R 0.64 0.09 0.31 0.06 plt 0.05
• Clinical 1.1 0.11 0.28 0.07 p0.01
• Conclusions
• Dexamethasone reduced AMS symptom scores during
  decompression.
• Dexamethasone associated with decreased retinal
  artery width.
• No side effects noted.
• What about real altitude? Rebound effects? Longer
  exposures?
• What about those individuals who did not complete
  crossover?

Tal, 1680m
25
AMS - Prevention acetazolamide vs. dexamethasone

• Reid et al. Acetazolamide or dexamethasone for
  prevention of acute mountain sickness a
  meta-analysis. J Wild Med, 1994.
• Methods
• Computerized lit search, 23 databases and
  contacted authors. N 20.
• Placebo controlled trials acetazolamide or
  dexamethasone for AMS prophylaxis.
• Studies evaluated by 2 reviewers, quality
  assessed by Chalmers criteria and weighted
  accordingly.
• Outcomes incidence of AMS, AMS score by ESQ and
  GHAQ, and symptoms of AMS.
• Acetazolamide dose ranges 500-750mg qd, one
  study used 1000mg.
• Dexamethasone dose ranges 0.25mg q12 - 4mg
  q6-8h.

Tal, 1680m
26
AMS - Prevention acetazolamide vs. dexamethasone

• Reid et al. 1994.
• Results
• ES acetazolamide vs. placebo (n680) -0.61
  (-0.29 to -0.93)
• ES dexamethasone vs. placebo (n237) -0.32
  (0.38 to -1.02)
• ES for chamber studies much greater than field
  studies (-2.4 vs -0.5) however higher doses,
  greater ascent rates. Dexamethasone seemed more
  effective than acetazolamide in chamber studies
  only.
• Conclusions
• AMS prophylaxis with acetazolaminde or
  dexamethasone effective.
• ES greater for acetazolamide however,
  comparisons were not under same experimental
  conditions from study to study and dosages
  varied.
• Field studies favored acetazolamide, chamber
  studies dexamethasone.
• Given efficacy of acetazolamide and benign side
  effect profile compared to dexamethasone,
  acetazolamide should probably be the agent of
  choice for chemoprophylaxis dexamethasone for
  very rapid ascent rates (i.e. rescue or military
  operations).

Tal, 1680m
27
AMS - Prevention nifedipine

• Hohenhaus E et al. Nifedipine Does Not Prevent
  Acute
• Mountain Sickness. Am J Resp Crit Care Med 1994.
• Hypothesis
• Because AMS and HAPE share common
  pathophysiologic mechanisms nifedipine may be
  beneficial in the prevention of AMS as it is
  effective in the prophylaxis and treatment of
  HAPE.
• Methods
• RCT, n 27 HAPE-R mountaineers, rapid ascent to
  4559m.
• Nifedipine SR 20mg tid vs placebo.
• Results
• Subjects with AMS had significantly lower O2 sat
  (75.9 1.5 vs. 82 1.4), higher A-a gradients
  than asymptomatic subjects. PAP and PCO2 did not
  differ significantly between subjects with AMS
  and without.

Bagarchhap, 2080m
28
AMS - Prevention nifedipine

• Hohenhaus E et al. 1994.
• AMS scores were almost identical btw nifedipine
  and control subjects.
• Nifedipine was associated with significantly
  lower PAP pressures. No hypotension occurred.
• Nifedipine had no effect on O2 sat.
• Conclusions
• Nifedipine is ineffective for AMS prevention, or
  has a marginal benefit not detected with this
  study.
• The exaggerated hypoxemia seen with AMS in
  contrast to subjects who are well at altitude
  cannot be explained by changes in PAP, as no
  significant different in PAP was noted btw AMS
  and well subjects. This could be explained by V/Q
  mismatch, interstitial edema or lower hypoxic
  ventilatory drive (trend towards higher PCO2.)

Bagarchhap, 2080m
29
AMS - Prevention Antioxidants

• Bailey et al. Acute Mountain Sickness
  Prophylactic
• Benefit of Antioxidant Vitamin Supplementation at
  High
• Altitude. High Alt Med Biol, 2001.
• Hypothesis Free-radical mediated damage to BBB
  may be implicated in pathophysiology of AMS.
  Benefit of dexamethasone may be related to
  antioxidant properties which helps maintain BBB
  vascular integrity.
• Methods
• RCT, double-blinded, placebo controlled, n18.
• AO (ascorbic acid, dl-? tocopherol, ? -lipoic
  acid) qid vs placebo starting 3 wks prior ascent,
  continued until 10d at altitude (5180m)
• Results
• Trend towards decreased incidence of AMS in AO
  (5/9) vs. 9/9 in the placebo group (NS).
• AMS scores 2.3 0.9 in AO vs. 3.5 0.4 in
  placebo grp (p0.03).

Bagarchhap, 2080m
30
AMS - Prevention Antioxidants

• Bailey et al. 2001.
• Higher O2sat in the AO group (89 5 vs. 85
  5, p0.04)
• Lower satiety scores and higher caloric intake in
  the AO group-however, did not measure baseline
  satiety or caloric intake at sealevel.
• Conclusions
• This study indicates that AO may be effective in
  preventing AMS as well as reducing symptom scores
  ? via AO mediated improvement in BBB integrity?
• Possible hyperphagic effect?
• No side effects reported.
• Larger studies warranted.

Bagarchhap, 2080m
31
AMS - Prevention

• Dumont et al. Efficacy and harm of
  pharmacological prevention of acute mountain
  sickness quantitative systematic review. BMJ
  2000.
• Methods
• Systematic Search for all RTCs on efficacy and
  harm of pharmacological prevention of AMS.
• 33 trials, n 523 pharmacologic intervention, n
  519 placebo
• Endpoints prevention of AMS prevention of AMS
  sxs.
• Results
• Final altiudes 4050 - 5885m. Mean AMS
• event rate 67.
• Incidence correlated with rate of ascent,
• not final altitude
• NNTs high with low ascent rates
• decreased with increasing altitudes.

Ascent rate (m/h)
AMS incidence in control groups
Manang, 3440m
32
AMS - Prevention

• Dumont et al. BMJ 2000
• Meta-anlysis - dexamethasone
• 8 trials, mean altitude 4000m.
• 0.5-2mg qd had no effect on AMS.
• 8-16mg qd was effective in preventing AMS.
• RR 2.5 (CI 1.7-3.6) NNT 2.8 (2.0-4.6).
• Trend towards decreasing headache and nausea, not
  statistically significant. Significant decrease
  in dizziness RR 2.14 (1.01-4.5).
• Adverse reactions when weaned RR 4.45 (1.9-9.3),
  
• NNT 3.7.
• Adverse reactions depression.

Manang, 3440m
33
AMS - Prevention

• Dumont et al. BMJ 2000
• Meta-anlysis - acetazolamide
• 9 trials, mean altitude 4478m.
• 500mg trend towards less AMS RR 1.2 (0.93-1.59)
  NNT 7(3.3-54).
• 750mg decreased AMS RR 2.18 (1.5-3.1) NNT 2.9
  (2.0-5.2).
• Bias lower ascent rates used for 500mg, making
  500mg less likely to work.
• Significant less insomnia, headache and nausea
  than placebo.
• Significantly more adverse drug effects
  polyuria, paresthesias and taste disturbance than
  placebo groups.
• Conclusion
• Dexamethasone 8-16mg qd and acetazolamide 750mg
  qd equally effective in preventing AMS above
  4000m with ascent rates gt500m/day (NNTs lt 3).
• Prophylaxis is worth while when ascent rates are
  high.

Manang, 3440m
34
AMS - Prevention
Dexamethasone

• Dumont et al. BMJ 2000

Incidence of AMS in placebo groups
other drugs
Acetazolamide
Incidence of AMS in intervention group
Manang, 3440m
35
AMSTreatment

• Oxygen, carbon dioxide enriched air
• Descent
• Dexamethasone
• Acetazolamide
• Symptomatic treatment

Gangapurna, 7454m
36
AMS - treatment Gamow Bag

• Early uncontrolled studies in Himalayan trekkers
  indicated short and long term benefit of portable
  hyperbaric chambers in the treatment of AMS.
• Pollard. Treatment of acute mountain sickness.
  BMJ 1995.
• Lay press anecdotal reports of symptomatic
  relief has led to widespread use of portable
  hypobaric chambers by trekking/expedition
  companies.
• Unfortunately, there is confusion among the
  public about the therapeutic role of these
  portable hypobaric chambers. At least one
  potentially avoidable death has occurred. In 1991
  a European trekker died at 5100, in Nepal after
  three days of intermittent treatment in a
  portable hyperbaric chamber without an attempt at
  descent. Descent might have been life saving.

Gangapurna, 7454m
37
AMS - treatment Gamow Bag

• Bärtsch et al. Treatment of acute mountain
  sickness by simulated descent a randomised
  controlled trial. BMJ 1993.
• Hypothesis
• Hyperbaric tx reduces the symptoms of AMS - for
  how long? rebound?
• Methods
• Single-blinded RTC.
• n 64 mountaineers exposed to 4559m (430 mm Hg)
  with AMS.
• One hour of treatment in a portable hyperbaric
  chamber at 193mbar (simulated descent of 2250m)
  vs. treatment in a portable hyperbaric chamber at
  20mbar (300m, control) vs. bed rest.
• Outcomes AMS symptoms before, immediately after
  and 12h post tx.
• Intake of analgesics and antiemetics.

Gangapurna, 7454m
38
AMS - treatment Gamow Bag

• Bärtsch et al. 1993
• Results
• Increase in O2 sat in tx group and short-term
  improvement in AMS score
• 193mbar 20mbar rest
• O2 sat during 90(88-91) 70(67-75) 68
  (61-75 ) (plt0.001)
• O2 sat 12h post 72(68-76) 74 (70-77)
  74(70-79)
• AMS prior tx 4.1(3.7-4.5) 4.3 (3.7-4.8) 4.5
  (4.0-5.0)
• AMS after tx 1.4 (1.1-1.6) 2.7 (2.1-3.4)
  2.7 (2.1-3.3) (plt0.001)
• AMS 12h post 2.5 (1.8-3.2) 3.1 (2.4-3.9)
  2.3 (2.1-3.3)
• Conclusion
• Portable hyperbaric chambers can alleviate AMS
  symptoms and hypoxia rapidly but have no
  prolonged effect.on AMS or oxygenation.
• Chambers should be used only to FACILITATE but
  NOT delay descent.
• Prolonged tx? Repeated tx? Rebound?

Gangapurna, 7454m
39
AMS - treatment simulated descent vs.
dexamethasone

• Keller et al. Simulated descent v dexamethasone
  in treatment of acute mountain sickenss a
  randomised trial. BMJ 1995.
• Methods
• RTC non-blinded.
• n31 mountaineers with AMS at 4559m.
• Random assignment to hyperbaric chamber (193mbar,
  2250m descent) for one hour vs. dexamethasone 8mg
  first dose, then 4mg q6h.
• Outcome AMS symptoms at 1hour and 11h.
• Results
• 1h Trend towards greater relief of AMS at one
  hour with hyperbaric tx (- 4.0 1.9 vs. - 2.5
  1.8) as opposed to Dexamethasone.

Letdar, 4230m
40
AMS - treatment simulated descent vs.
dexamethasone

• Keller et al. 1995.
• 11h Dexamethasone group suffered significantly
  less AMS than the hyperbaric tx group (-7.0
  3.6 vs. -1.6 3.0)
• O2 sat Trend towards increasing sat with
  dexamethasone at 11h.
• Similar intake of analgesics.
• Conclusion
• Hyperbaric treatment has a short-term beneficial
  effect on AMS, but no long term effect.
• Dexamethasone has less short-term but a longer
  term clinical improvement.

Letdar, 4230m
41

AMS - treatment Acetazolamide

• Grissom et al. Acetazolamide in the Treatment of
  Acute
• Mountain Sickness Clinical Efficacy and Effect
  on Gas
• Exchange. Ann Int Med, 1992.
• Methods
• RCT, placebo controlled, double-blinded, n12
  with AMS who presented to a medical research
  center at 4200m on Mt McKinley.
• Acetazolamide 250mg q8h, 2 doses vs. placebo.
• Results
• At 24h 1/6 climbers receiving acetazolamide vs.
  6/6 receiving placebo still met criteria for AMS
  (p0.015).
• PaO2 improved in acetazolamide group and worsened
  in placebo group (2.9 0.8mmHg vs. -1.3
  2.8mmHg, p0.045).
• Conclusions
• In AMS acetazolamide relieves symptoms and
  improves oxygenation.

High Camp, 4750m
42
HAPE - Epidemiology

• Most common fatal manifestation of altitude
  illness.
• 1-2 of healthy individuals which ascending over
  4000m.
• 10 of HAPE-R and 60 of HAPE -S individuals who
  ascend to over 4000m in 24h develop HAPE.
• Risk factors
• Strenuous exercise - absence of pulmonary artery
• Cold - pulmonary hypertension
• Recent URTI - reentry
• Prior HAPE
• (Bärtsch et at. 1991)

On the way to Thorung La 5000m
43
HAPE - signs symptoms

• Symptoms most often superimposed on AMS
• Cough - Tachypnea - SOBOE, rest
• Tachycardia - Orthopnea - Fever
• Cyanosis - Rales - Watery sputum
• 2-4d after rapid ascent, often during the night.
• CXR (fluffly patchy perihilar infiltrates,
  sparing of lung bases periphery, usually
  affects the RML first.
• ECG RBBB, RAD, tall R precordial leads, S
  lateral leads.
• (Jerome Severinghaus, 1996.)

On the way to Thorung La 5000m
44
HAPE - signs symptoms

• In those with HAPE severe hypoxemia can lead to
  the rapid progression of AMS to HACE.
• Mortality
• 11 with treatment.
• when descent impossible and no supplemental O2
  available mortality rate 44 - 50.
• An effective portable medical regimen for the
  treatment of HAPE is desirable for when immediate
  descent it not an option.
• (Oelz et al, 1989 Bärtsch et al. 1991, Hackett
  Roach, 2001)

On the way to Thorung La 5000m
45
HAPE - prevention

• Slow ascent (HAPE-S lt300m/day over 2000m)
• Nifedipine
• Garlic

Thorung La, 5415m
46
HAPE - prevention

• Bärtsch P et al. Prevention of High Altitude
  Pulmonary Edema by Nifedipine. NEJM 1991.
• Methods
• RCT, double blinded, n 21 with prior hx of HAPE
  acscent to 4559m.
• Nifedipine SR 20mg q8h vs. placebo 3d prior
  ascent to 4th day at altitude.
• Results
• 7/11 subjects with placebo vs. 1/10 with
  nifedipine developed HAPE (p0.01).
• Placebo arm terminated early because too sick, 2
  of developed HACE.
• Significantly lower PAPs (41 8 vs. 53
  16mmHg), A-a gradients (6.6 3.8 vs. 11.8 4.4)
  and lower symptom scores with nifedipine. Trend
  towards higher O2sat with nifedipine.
• Conclusions
• Nifedipine prophylaxis lowers PAP and HAPE
  incidence when taken prophylactically in HAPE S
  individuals. No side effects reported.

Thorung La, 5415m
47
HAPE - prevention

• Fallon et al. Garlic prevents hypoxic pulmonary
  hypertension in rats. Am. J. Physiol. 1998.
• Hypothesis Hypoxic pulmonary vasoconstriction
  underlies the development of HAPE. Anecdotal
  evidence suggest a benefit of garlic in
  preventing altitude induced symptoms.
• Methods Gave rats garlic gavage (100mg/kg body
  weight!) for 5 days, then subjected them to
  normobaric hypoxia.
• Results Complete inhibition of acute hypoxic
  pulmonary vasoconstriction in garlic gavage group
  compared with controls. Nitric oxide synthase
  inhibitor inhibited the vasodilatory effects of
  garlic.
• Conclusion Garlic may prevent hypoxic pulmonary
  vasoconstriction by upregulating NO synthesis.
  Garlic may be beneficial in HAPE.

Thorung La, 5415m
48
HAPE - treatment

• Descent
• Postural Maneuver
• Oxgen
• NO
• Nifedipine
• EPAP

Heading towards Muktinath, 5000m
49
HAPE - postural drainage?

• Bock et al. Emergency Maneuver in High-Altitude
• Pulmonary Edema. JAMA 1986.
• 33yr old mountaineer with prior hx of HAPE
  trekking at 5100m.
• SOB, cough,watery sputum, felt as if he were
  drowning and that death was imminent
• Evacuation route involved crossing over a 5800m
  pass.
• Relieved when kneeling with head on the ground
  and his buttocks in the air, his trunk upside
  down.
• He got his companion to straddle him, applying
  pressure on abdomen which with a deep breath
  triggered paroxysm of cough and increase sputum
  volume. After 20-30minutes of coughing, felt less
  SOB.

Heading towards Muktinath, 5000m
50
HAPE - treatment O2 vs. NO

• Anand et al. Effects of Inhaled Nitric Oxide and
  Oxygen
• in High-Altitude Pulmonary Edema. Circulation
  1998.
• Methods
• RTC - NO vs. oxygen vs. NO oxygen.
• N 14 soldiers with HAPE transported to a high
  altitude research center and hospital at 3600m in
  t Western Himalayas.
• Each patient was exposed to the 3 gas mixtures
  for 30min sequentially with washout periods of
  room air. Measurements were performed in the last
  10min of each gas inhalation. After the protocol
  was over all patients were treated with oxygen
  and descent.
• Results
• NO inhalation reduced PAP by 11mmHg 1.5, and
  pulmonary vascular resistance by 36. O2sat
  increased from 67 3.5 to 72 3.6.
• FiO2 50 caused a greater rise in O2sat than NO,
  but a similar drop in PAP.

Heading towards Muktinath, 5000m
51
HAPE - treatment O2 vs. NO

• Anand et al. 1998.
• NO with FiO2 of 50 caused the largest decrease
  in PAP (36 2.4 vs. 16 1.7mmHg) and greatest
  rise in O2sat (68 3.6 vs. 96 1.3) - although
  this treatment was 3h into the treatment
  protocol.
• Conclusions
• NO and oxygen may have additive effects in the
  treatment of HAPE.

Heading towards Muktinath, 5000m
52
HAPE - treatment NO

• Oelz et al. Nifedipine for High Altitude
  Pulmonary
• Edema. Lancet, 1989.
• Methods
• n6 subjects with HAPE, 12-36hrs after ascent to
  4559m in 24h.
• All subjects were treated with Nifedipine 10mg
  S/L and 20mg po q6h. If SBP did not drop by
  10mmHg after the first dose another 10mg S/L was
  administered.
• Controls with AMS but no HAPE!
• Results
• Drop in AMS score from 9.2 ( 1.6) pretx to 5.7
  ( 1.8) at 1h, and 2.5
• ( 0.8) 14h post tx (plt0.001).
• O2 sat 65 pretx to 73 1h post tx to 69 14h
  post tx (NS).

above Muktinath, 4800m
53
HAPE - treatment nifedipine

• Oelz et al. 1989.
• PAP decreased with nifedipide from 133mmHg pretx
  to 73mmHg 1h post tx, to 58mmHg 14h post tx.
• (Controls without HAPE had PAPs of 63mmHg.)
• Radiographic scores decreased from 7.7 to 4.0 14h
  post tx (plt0.05).
• All subjects with HAPE reported SOB and chest
  pressure prior tx, which was relieved 1h post
  nifedipine.
• Subjects were able to continue mountain climbing
  activities.
• Conclusion
• Nifedipine may be effective.
• Properly controlled, randomised studies are
  needed.

above Muktinath, 4800m
54
HAPE - treatment CPAP

• Schoene et al. High Altitude Pulmonary Edema and
  Exercise at 4400m on Mount McKinnley Effect of
  Positive Airway Pressure. Chest, 1985.
• Methods
• n4 climbers with HAPE, n12 healthy climbers at
  4400m.
• All sujects put on EPAP, healthy subjects made to
  exercise, HAPE subjects rested.
• Mask on with no end expiratory pressure vs. 5 and
  10cm H2O.
• Results
• EPAP increased O2 sat in HAPE subjects (54 to
  61, p0.005) as well in healthy subjects (85 to
  88, plt0.01).
• Conclusions
• Positive end expiratory pressure may be
  beneficial in HAPE.

above Muktinath, 4800m
55
HACE - epidemiology, pathophysiology

• Fatal HACE has been reported as low as 2500m.
• lt1 of mountain climbers.
• AMS may progress to HACE in 12h.
• Develops 1-9days after ascent.

56
HACE - signs and symptoms

• Preexisting AMS or HAPE with severe h/a, n/v
• Ataxia (cerebellar) - sensitive sign for early
  recognition
• Altered level of consciousness, global
  encephalopathy.
• seizures
• Focal neurological signs, cranial nerve palsies,
  slurred speech
• Associated with retinal hemorrhages
• Papilledema, elevated ICP
• Cuase of death herniation
• (Hackett Roach, 2001)

Muktinath, 3760m
57
HACE - prevention

• As for AMS - graded ascent most important

Muktinath, 3760m
58
HACE - treatment

• Immediate descent
• Bed rest
• Hyperbaric Chamber
• Oxygen
• Dexamethasone 8mg IV, then 4mg q6h
• Measures to decrease ICP once in hospital center

Manang valley, 3000m
59
HACE - treatment

• Dexamethasone 8mg IV, then 4mg q6h
• Supportive therapy
• Anecdotal reports only
• May work by improving capillary membrane
  integrity and causing vasoconstriction.
• (Levine et al, 1989)

Manang valley, 3000m
60
Thorung La, 5415m
AMS Prevention
Graded Ascent Prior hypoxic exposure Oxygen N
ifedipine Dexamethasone Furosemide,
Spironolactone Antioxidants Narcotics Acetazola
mide ADH
61
Thorung La, 5415m
AMS Treatment

Oxygen CO2 enriched air Descent symptomatic
therapy Dexamethasone nifedipine Acetazolamide
62
Thorung La, 5415m
HAPE Prevention

Slow ascent (HAPE-S lt300m/day over
2000m) Nifedipine Garlic
63
Thorung La, 5415m
HAPE Treatment

Descent EPAP Postural Maneuver Nifedipine Oxgen
NO
64
Thorung La, 5415m
HACE Prevention Treatment

AMS Dexamethasone Supportive therapy
65
(No Transcript)
66

• References
• Anand I, Prasad B, Chugh S, Rao K, Cornfield D,
  Milla C, Singh N, Singh S W Selvamurthy.
  Effects of Inhaled Nitric Oxide and Oxygen in
  High-Altude Pulmonary Edema. Circulation 1998
  982441-2445.
• Bärtsch P, Baumgartner R, Waber U, Maggiorini M
  O Oelz. Comparison of carbon-dioxide-enriched,
  oxygen-enriched, and normal air in treatment of
  acute mountain sickenss. Lancet 1990
  336772-775.
• Bärtsch P, Eichenberger U, Ballmer P, Gibbs J,
  Schirlo C, Oelz O E Mayatepek. Urinary
  Leukotriene E4 Levels Are Not Increased Prior to
  High-Altitude Pulmonary Edema. Chest 2000 117,
  5.
• Bärtsch P, Grünig E, Hohenhaus E C Dehnert.
  Assessment of High Altitude Tolerance in Healthy
  Individuals. High Alt Med Biol 2001, 2,
  2287-295.
• Bärtsch P, Maggiorini M, Ritter M, Noti C, Vock P
  O Oelz. Prevention of High-Altitude Pulmonary
  Edema by Nifedipine. NEJM 1991 3251284-1289.
• Bärtsch P, Merki B, Hofstetter D, Maggiorini M,
  Kayser B O Oelz. Treatment of acute mountain
  sickness by simulated descent a randomised
  controlled trial. BMJ 19933061098-1101.
• Burse R V Forte. Acute Mountain Sickness at
  4500m Is Not Altered by Repeated Eight-Hour
  Exposures to 3200-3550m Normobaric Hypoxic
  Equivalent. Aviat Space Environ Med 1988 59
  942-949.
• Busch T, Bärtsch P, Pappert D, Grünig E,
  Hildebrandt W, Elser H, Falke K E Swenson.
  Hypoxia Decreases Exhaled Nitric Oxide in
  Mountaineers Susceptible to High-Altitude
  Pulmonary Edema. Am J Resp Crit Care Med 2001
  163368-373.
• Basnyat B, Lemaster J J Litsch. Everest or
  Bust A cross Sectional, Epidemiological Study of
  AMS at 4243Meters in the Himalayas. Aviat Space
  Environ Med 1999 70 867-873.
• Burtscher M, Likar R, Nachbauer W M Philadelphy.
  Aspirin for prophylaxis against headache at high
  altitudes randomised, double blind, placebo
  controlled trial. BMJ 1998 316 1057-1058.
• Dumont L, Mardirosoff C M Tramèr. Efficacy and
  harm of pharmacological prevention of acute
  mountain sickness a quantitative systematic
  review. BMJ 2000 321 267-271.
• Duplain H, Sartori C, Lepori M, Egli M, Allemann
  Y, Nicod P U Scherrer. Exhaled Nitric Oxide in
  High-Altitude Pulmonary Edema. Am J Resp Crit
  Care Med 2000 162221-224.
• Duplain H, Vollenweider L, Delabays A, Nicod P,
  Bärtsch P U Scherrer. Augmented Sympathetic
  Activation During Short-Term Hypoxia and
  High-Altitude Exposure in Subjects Susceptible to
  High-Altitude Pulmonary Edema. Circulation 1999
  99 1713-1718.

67

• Ellsworth A, Larson E D Strickland. A
  Randomized Trial of Dexamethasone and
  Acetazolamide for Acute Mountain Sickness
  Prophylaxis. Am J Med 1987 83 1024-1030.
• Fagan K J Weil. Potential Genetic Contributions
  to Control of the Pulmonary Circulation and
  Ventilation at High Altitude. High Alt Med Biol,
  2001 2, 3 165-171.
• Fallon M, Abrams G, Abdel-Razek T, Dai J, Chen
  SJ, Chen YF, Luo B, Oparil S D Ku. Garlic
  Prevents hypoxic pulmonary hypertension in rats.
  Am J Physiol 1998 275L283-L287.
• Ferrazzini G, Maggiorini M, Kriemler S, Bärtsch P
  O Oelz. Successful treatment of acute mountain
  sickness with dexamethasone. BMJ 1987 294
  1380-1987.
• Forwand S, Landowne M, Follansbee J J Hansen.
  Effect of Acetazolamide of Acute Mountain
  Sickness. NEJM 1968279839-844.
• Hackett P. Pharmacological prevention of acute
  mountain sickness. BMJ 2001 322 48.
• Hackett P, Rennie D H Levine. The incidence,
  importance and prophylaxis of acute mountain
  sickness. Lancet 1976ii1149-1154.
• Hackett P R Roach. High-Altitude Illness. NEJM
  2001 345, 2107-114.
• Hacket P, Roach R, Wood R, Foutch R, Meehan R,
  Rennie D W Mills. Dexamethasone for Prevention
  and Treatment of Acute Mountain Sicknss. Aviat
  Space Environ Med 1988 59950-954.
• Hackett P, Yarnell P, Hill R, Reynard K, Heit J
  J McCormick. High-Altitude Cerebral Edema
  EvaluatedWith Magnetic Resonance Imaging. JAMA
  1998 280, 221920-1925.
• Hanaoka M, Kubo K, Yamazaki Y, Miyahara T,
  Matsuzawa Y, Kobayashi T, Sekiguchi M, Ota M H
  Watanabe. Association of High-Altitude Pulmonary
  Edema With the Major Histocompatibility Complex.
  Circulation, 1998 97 1124-1128.
• Hanaoka M, Tanaka M, Ge RL, Droma Y, Ito A,
  Miyahara T, Koizumi T, Fujimoto K, Fujii T,
  Kobayashi T K Kubo. Hypoxia-Induced Pulmonary
  Blood Redistribution in Subjects With a History
  of High-Altitude Pulmonary Edema. Circulation
  2000 101 1418-1422.
• Hanaoka M, Kubo K, Yamazaki Y, Miyahara T,
  MatsuzawaY, Kobayashi T, Sekiguchi M, Ota M H
  Watanabe. Association of High-altitude Pulmonary
  Edema With the Major Histocompatibility Complex.
  Circulation 1998 97 1124-1128.
• Hohenhaus E, Niroomand F, Goerre S, Vock P, Oelz
  O P Bärtsch. Nifedipine does not prevent acute
  mountain sickness. AM J Respir Crit Care 1994
  150 857-860.
• Houston C. Incidence of acute mountain sickness.
  Amer Alpine J 1985 27162-165.
• Hultgren H. High-Altitude Pulmonary Edema. Annu
  Rev Med 1996 47267-284

68

• Jansen G, Krins A, Basnyat B, Bosch A J Odoom.
  Cerebral Autoregulation in Subjects Adapted and
  Not Adapted to High Altitude. Stroke 2000 31
  2314-2318.
• Jerome E J Severinghaus. High-Altitude
  Pulmonary Edema. NEJM 334 662-664.
• Johnson T, Rock P, Fulco C, Trad L, Spark R J
  Mahler. Prevention of Acute Mountain Sickness by
  Dexamethasone. NEJM 1984 310 683-686.
• Keller HR, Maggiorini M, BärtschP O Oelz.
  Simulated descent versus dexamethasone in
  treatment of acute mountain sickness a
  randomised trial. BMJ 1995 310 1232-1235.
• Levine B, Yoshimura K, Kobayashi T, Fukushima M,
  Shibamoto T G Ueda. NEJM 1989 321, 25
  1707-1713.
• Lundby C, Araoz M G Van Hall. Peak Heart Rate
  Decreases with Increasing Severity of Acute
  Hypoxia. High Alt Med Biol 2001 2, 3 369-376.
• Krieger B R de la Holz. Altitude-Related
  Pulmonary Disorders. Crit Care Clinics 1999 15,
  2265-280.
• Maggiorini M, Bühler B, Walter M O Oelz.
  Prevalence of acute mountain sickness in the
  Swiss Alps. BMJ 1990 301853-855.
• Maggiorini M, Mélot C, Pierre S, Pfeiffer F,
  Greve I, Sartori C, Lepori M, Hauser M, Scherrer
  U R Naeije. High-Altitude Pulmonary Edema Is
  Initially Caused by an Increase in Capillary
  Pressure. Circulation 2001 103 2078-2083.
• Maloney J, Wang D, Duncan T, Voekel N S Ross.
  Plasma Vascular Endothelial Growth Factor in
  Acute Mountain Sickness. Chest 2000 118xxxxx
• Montgomery A, Mills J J Luce. Incidence of
  acute mountain sickness at intermediate altitude.
  JAMA 1989 261732-734.
• Oelz O, Ritter M, Jenni R, Maggiorini M, Waber U,
  Vock P P Bärtsch. Nifedipine for High Altitude
  Pulmonary Oedema. Lancet 1989 1241-1244.
• Pollard A. Treatment of acute moutnain sickness.
  BMJ 1995 311 629.
• Reid D, Carter K A Ellsworth. Acetazolamide
  ordexamethasone for prevention of acute mountain
  sickness a meta-analysis. J Wild Med,1994
  534-48.
• Roach R, Maes D, Sandoval D, R Robergs, M
  Icenogle, H Hirghofer, D Lium J Loeppky.
  Exercise exacerbates actue mountain sickness at
  simulated high altitude. J of Appl Physiol 2000
  88 581-585.
• Scherrer U, Vollenweider L, Delabays A, Savcic M,
  Eichenberger U, Kleger GR, Fikrle A, Ballmer P,
  Nicod P P Bärtsch. Inhaled Nitric Oxide for
  High-Altitude Pulmonary Edema. NEJM 1996 334
  624-629.
• Schoene R, Swenson E, Pizzo C, Hackett P, Roach
  R, Mills W, Henderson W T Martin. The lung at
  high altitude bronchoalveolar lavage in acute
  mountain sickness and pulmonary edema. J Appl
  Physiol 1988 64,6 2605-2613.