Altitude Medicine updates and controversies… Corinne Michèle Hohl R3 Royal College Emergency Medicine Training Program

Altitude Medicine updates and controversies…

Corinne Michèle Hohl R3 Royal College Emergency

Medicine Training Program

•Millions of visitors per year to high altitude

destinations world wide, increasing trends:– >20’000 British trekkers to Nepal annually

– 90’000 nights spent in huts > 2500m in Switzerland/yr

•Ski industry.•Aviation industry.•Pathophysiologic modelling of hypoxic processes in health indivisuals.•Military operations.

Thorung La Pass, 5467m

Physics

Himalayan Peaks over Kathmandu, Nepal

Physics

Hypobaric hypoxiaAlveolar gas equation:

PAO2 = [(PB-PH2O) * FiO2 - PaCO2 /R + (0.003*PaO2)]

PAO2 varies proportionally to PB, as it declines PaO2declines.


Physics

Further from the earth’s 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%

.


Adaptive mechanisms

• As PaO2 declines to 60mmHg chemosensors in the carotid body trigger an increase in minute ventilation:

Hypoxic Ventilatory vesponse (HVR)• PCO2 drops --> resp alkalosis --> limits HVR.• Low HVR at SL predicts increased

susceptibility. (Krieger & Holz, 1999, Fagan & Weil, 2001)


• 24-48h: bicarbonate diuresis --> compensatory metabolic acidosis --> minute ventilation increases.

• Catecholmine release --> 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)


Adaptive mechanisms

AMSAcute

Mountain

SicknessTrekkers on the Annapurna Circuit

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

AMS - Pathophysiology

AMS Pathophysiologycerebral 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 --> 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 individual’s adaptability to impaired CA?

AMS Pathophysiology cerebral autoregulation

AMS - Signs & Symptoms

Lake Louise Consensus 1993:• Headache in an unacclimatized individual who recently

arrived at > 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


Risk factors:– Prior history– Residence below 900m– Exertion– Preexisting cardiopulmonary disorders– Younger individuals (<50) – Men more susceptible to HAPE but not AMS– Dehydration

(Hackett & Roach, 2001, Basnyat, 1999) Machhapuchhre, 6993m


Fitness is NOT protective:Roach et al. 2000:

– Cross-over design, n=7, 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


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 < 300m/day above 2000m in first exposure to altitude or susceptible individuals.

(Bärtsch P et al. 2001) Machhapuchhre, 6993m

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

• Graded Ascent• Prior hypoxic exposure

• Oxygen• Acetazolamide

• Dexamethasone• Nifedipine

• AntioxidantsBhulebhule, 840mBhulebhule, 840m

AMSAMS

PreventionPrevention

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.

AMS - Prevention: normobaric hypoxia

Bhulebhule, 840mBhulebhule, 840m

Forwand et al. Effect of Acetazolamide on Acute Mountain Sickness. NEJM 1968.

Hypothesis: • Studies in the 30’s 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 12’800 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.

AMS - Prevention: Acetazolamide




HCOHCO33

Blood pCOBlood pCO22

pHpH

AcetazolamideAcetazolamide



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 Bhulebhule, 840m

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. • n=12; 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.

AMS - Prevention: Dexamethasone

Tal, 1680mTal, 1680m

Johnson et al. 1984.Results: Placebo Dexanethasone

AMS - C 1.09 + 0.18 0.26 + 0.08 p< 0.05

AMS -R 0.64 + 0.09 0.31 + 0.06 p< 0.05

Clinical 1.1 + 0.11 0.28 + 0.07p=0.01

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?

AMS - Prevention: 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 Chalmer’s

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.

AMS - Prevention: acetazolamide vs. dexamethasone


Reid et al. 1994.Results:• ES: acetazolamide vs. placebo (n=680): -0.61 (-0.29 to -0.93)• ES: dexamethasone vs. placebo (n=237): -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).

AMS - Prevention: acetazolamide vs. dexamethasone


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.

AMS - Prevention: nifedipine

Bagarchhap, 2080mBagarchhap, 2080m

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.)

AMS - Prevention: nifedipine


Bailey et al. Acute Mountain Sickness; ProphylacticBenefit 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, n=18.• 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 (p=0.03).


AMS - Prevention: Antioxidants

Bailey et al. 2001.

• Higher O2sat in the AO group (89 + 5% vs. 85 + 5%, p=0.04)• 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.


AMS - Prevention: Antioxidants

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 RTC’s 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:• NNT’s high with low ascent rates

decreased with increasing altitudes.

Manang, 3440mManang, 3440m

AscenAscent rate t rate (m/h)(m/h)

AMS AMS incidence incidence in control in control

groupsgroups

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.


AMS - Prevention


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 >500m/day (NNTs < 3).

• Prophylaxis is worth while when ascent rates are high.


AMS - Prevention



Incidence of Incidence of AMS in placebo AMS in placebo

groupsgroups

Incidence of AMS Incidence of AMS in intervention in intervention

groupgroup

DexamethasoneDexamethasone


other other drugsdrugs

AMSTreatment

• Oxygen, carbon dioxide enriched air

• Descent• Dexamethasone• Acetazolamide• Symptomatic treatment Gangapurna, 7454mGangapurna, 7454m

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, 7454mGangapurna, 7454m


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.



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 ) (p<0.001)

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)

(p<0.001)

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?


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.

• n=31 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, 4230mLetdar, 4230m

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, 4230mLetdar, 4230m

Grissom et al. Acetazolamide in the Treatment of AcuteMountain Sickness: Clinical Efficacy and Effect on Gas

Exchange. Ann Int Med, 1992.Methods:• RCT, placebo controlled, double-blinded, n=12 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 (p=0.015).• PaO2 improved in acetazolamide group and worsened in placebo

group (+2.9 + 0.8mmHg vs. -1.3 + 2.8mmHg, p=0.045).Conclusions:• In AMS acetazolamide relieves symptoms and improves oxygenation.

AMS - treatment: Acetazolamide

High Camp, 4750mHigh Camp, 4750m

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 5000mOn the way to Thorung La 5000m

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.)


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)


HAPE - prevention

Slow ascent (HAPE-S <300m/day over 2000m)

Nifedipine

Garlic Thorung La, 5415mThorung La, 5415m

HAPE - preventionBärtsch 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

(p=0.01).• 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, 5415mThorung La, 5415m

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.


HAPE - treatment

Descent

Postural Maneuver

Oxgen

NO

Nifedipine

EPAPHeading towards Muktinath, 5000mHeading towards Muktinath, 5000m

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, 5000mHeading towards Muktinath, 5000m

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.


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.


HAPE - treatment: NO

Oelz et al. Nifedipine for High Altitude PulmonaryEdema. Lancet, 1989.

Methods:• n=6 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 (p<0.001).

• O2 sat: 65% pretx to 73% 1h post tx to 69% 14h post tx (NS).

above Muktinath, 4800mabove Muktinath, 4800m

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 (p<0.05).

• 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, 4800mabove Muktinath, 4800m

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:• n=4 climbers with HAPE, n=12 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%, p=0.005) as well in healthy subjects (85% to 88%, p<0.01).

Conclusions: • Positive end expiratory pressure may be beneficial in HAPE.

above Muktinath, 4800mabove Muktinath, 4800m

HACE - epidemiology, pathophysiology

• Fatal HACE has been reported as low as 2500m.

• <1% of mountain climbers.• AMS may progress to HACE in 12h.

• Develops 1-9days after ascent.

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, 3760mMuktinath, 3760m

HACE - prevention

As for AMS - graded ascent most important

Muktinath, 3760mMuktinath, 3760m

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, 3000mManang valley, 3000m

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, 3000mManang valley, 3000m


AMSAMSPreventionPrevention

Graded Ascent Prior hypoxic exposure

Oxygen Nifedipine

Dexamethasone Furosemide, Spironolactone

Antioxidants Narcotics

Acetazolamide ADH


AMSAMSTreatmentTreatment

Oxygen CO2 enriched air

Descent symptomatic therapy

Dexamethasone nifedipine

Acetazolamide


HAPEHAPEPreventionPrevention

Slow ascent (HAPE-S <300m/day over 2000m)

Nifedipine

Garlic


HAPEHAPETreatmentTreatment

Descent EPAP

Postural Maneuver Nifedipine

Oxgen NO


HACEHACEPreventionPrevention TreatmentTreatment

AMS Dexamethasone

Supportive therapy

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; 98:2441-2445.

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; 336:772-775.

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, 2:287-295.

Bärtsch P, Maggiorini M, Ritter M, Noti C, Vock P & O Oelz. Prevention of High-Altitude Pulmonary Edema by Nifedipine. NEJM 1991; 325:1284-1289.

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 1993;306:1098-1101.

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; 163:368-373.

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; 162:221-224.

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.

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; 275:L283-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 1968;279:839-844.

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 1976;ii:1149-1154.

Hackett P & R Roach. High-Altitude Illness. NEJM 2001; 345, 2:107-114.

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; 59:950-954.

Hackett P, Yarnell P, Hill R, Reynard K, Heit J & J McCormick. High-Altitude Cerebral Edema EvaluatedWith Magnetic Resonance Imaging. JAMA 1998; 280, 22:1920-1925.

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; 27:162-165.

Hultgren H. High-Altitude Pulmonary Edema. Annu Rev Med 1996; 47:267-284

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, 2:265-280.Maggiorini M, Bühler B, Walter M & O Oelz. Prevalence of acute mountain sickness in the Swiss Alps. BMJ 1990; 301:853-855.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; 118:xxxxxMontgomery A, Mills J & J Luce. Incidence of acute mountain sickness at intermediate altitude. JAMA 1989; 261:732-734.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; 5:34-48.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.

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Altitude Medicine updates and controversies… Corinne Michèle Hohl R3 Royal College Emergency Medicine Training Program