risiko höhenkrankheit prophylaxe und therapie - … · risiko höhenkrankheit prophylaxe und...
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Marco Maggiorini Medical Intensive Care Unit
University Hospital Zurich
Risiko Höhenkrankheit Prophylaxe und Therapie
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Risk High Altitude Illness: Prophylaxis and Treatment
• Agenda High altitude illness definition (summary) AMS & HAPE
AMS prevention and treatment − Risk assessment − Non-medical preventive options − Medical preventive and treatment options
HAPE prevention and treatment − Risk assessment − Non-medical preventive options − Medical preventive and treatment options
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High Altitude Illness Phenotype
Climbers arriving at the summit of the Mont Blanc (4807m)
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High Altitude illness First Report
Chinese Headache Mountain c. 30 BC
(Tseen Han Shoo Book 96) "...Again passing the Great Headache Mountains, the Little Headache mountain,
the Red Lands and the Fever Slope, men's bodies became feverish, they lose color and are attacked with headache and vomiting".
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High altitude illness: First Classification
Puna of normal type
Puna of nervous type
Puna of cardiac type
Ravenhill 1913
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High altitude illnesses: Contemporary Classification
Acute mountain sickness/HACE Axiatl T2-weighted MRI in HACE
Hackett et al JAMA 1998; 280: 1920-25
High altitude pulmonary edema
Excessive hypoxic pulmonary vasoconstriction
Edema of the splenium
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AMS-score 0 AMS-score 1-2 AMS-score > 3
Numbers od nights > 2500m 0-3 4-8 9-12 > 12
0
20
40
60
80
100
% o
f pat
ient
s
n = 421
Prevention of high altitude illness
100%
25%
49%
26%
100%
32%
49%
19%
100%
47%
40%
13%
100%
58%
36%
6%
Rate of ascent < 600 m / day
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Elite Mountaineers Expedition to Shisha Pagma 8005 m
Merz et al High Alt Med & Biol 2006
BC CI CII CIII
Ascent profile and SpO2 12 elite mountaineers
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AMS: Individual Susceptibility
AMS-score during the expedition to Chichapagma 8005m of 12 elite mountaineers: High individual variability of AMS incidence
Merz et al High Alt Med & Biol 2006
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Individual AMS susceptibility and succeeding at the Mont Aconcagua (6962m)
Pesce et al High Alt Med & Biol 2005, 6:258
Prevalence of AMS Summitters
Acclimatization and AMS incidence (days > 3000m/yr)
AMS History and AMS or probability to reach the summit
> 10 days > 3000m OR 0.60 (0.41 to 0.86)
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Prevalence of AMS (Lake Louise Score > 4) depending on history score in 555 mountaineers
1
9
3
12 12
27
0
5
10
15
20
25
30
History score < 4 History score ≥ 4
Perc
enta
ge (%
)
< 3000 m
3000 - 4000 m
> 4000 m
p < 0.01
p < 0.01
Schöb M. 2013
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Individual susceptibility is the major risk factor for AMS at 4559m
Schneider et al Med Sci Sports Exerc 2002,; 34:1886
Non susceptible Susceptible
Good acclimatisation
Intermediate acclimatisation
Poor acclimatisation
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Not being susceptible individuals climb faster at the Mount Aconcagua (6962m)
Rate of ascent ≥ 600 m • for AMS prevalence OR 0.71 (0.49 to 1.01) • Summitting OR 0.67 (0.47 to 0.96) No susceptible for AMS • for AMS prevalence OR 0.24 (0.17 to 0.35) • Summitting OR 1.64 (1.23 to 2.38)
Pesce et al High Alt Med & Biol 2005, 6:258
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Anecdotal experiences
Question: Does an average ascent rate of < 300m/day protect from AMS, HAPE and/or HAPE?
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Risk Assessment for high altitude illness
Low Moderate High
Adapted from Swenson & Bartsch NEJM 2013 368:2294
Risk Planned Ascent and Clinical History Low • Slow ascent (≤500 m/day above 2500 m);
• No history of AMS, HACE, or HAPE with previous exposure to similar altitude;
• Persons who are partially acclimatized (exposure to high altitudes of <3000 m in preceding weeks) planning a rapid ascent (>500 m/day below 4000 m)
Moderate • Unknown history of AMS, HACE, or HAPE and fast ascent (>500 m/day above 3000 m), i.e air craft, car, train
• History of AMS, HACE, or HAPE with previous exposure to high altitude that is similar to the planned ascent planning a slow ascent (≤500 m/day between 2500 and 4000 m) or who are partially acclimatized (exposure to high altitudes of >3000 m in preceding weeks)
High • Unknown history of AMS, HACE, or HAPE, very rapid ascent (considerably >500 m/day), and high final altitude (>4000 m);
• History of AMS, HACE, or HAPE with previous exposure to high altitude that is similar to the planned ascent without partial acclimatization
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Symptoms of acute mountain sickness
Excessive fatigue
Lassitude
Headache
Nausea, Vomiting
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Absolute increase in brain volume
AMS + (n = 10) AMS - (n = 10)
Bailey et al JCBFM 2006, 26:99
Pathophysiology of AMS: Brain swelling (edema) and microbleeds
Susceptibility weighted MRI in HACE
Schommer K. et al Neurology 81:1776
Microbleeds
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Pathophysiology of acute mountain sickness
Control of glycolisis by ADP, mitochondrial dys-function
Cellular osmolarity
CYTOTOXIC EDEMA
INTRACELLULAR EDEMA INTERSTITIAL EDEMA
HACE
AMS CEREBRAL DYSFUNCTION
Cytokines (IL1) Vascular-Endothelial-Growth-Factor Oxygen free radicals
CBF; Autoregulation Venous resistance Capillary pressure stress failure
VASOGENIC EDEMA & Microbleeding
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Drugs for prevention and treatment of acute mountain sickness (AMS)
• Symptomatic treatment Paracetamol, Aspirin, Ibuprofen Protone pump inhibitors Metoclopramid, Loperamid
• Prevention of acute mountain sicknss Acetazolamide
• Treatment of acute mountain sickness Acetazolamide (milde AMS) Dexamethasone (moderate to severe AMS)
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Mechanism of acetazolamide
Forwand et al. N Engl J Med 1968; 279: 839-45
Ventilation & PaO2 Metabolic acidosis
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Acetazolamide and altitude associeted periodic breathing
AC AL PL p value
AMS-R before 0.8±0.1 1.1±0.2 0.8±0.1 ns
after 0.6±0.1* 0.9±0.1 0.8±0.1 <0.05
PaO2 before 35±1 35±1 36±1 ns
after 41±1** 39±1** 38±2 ns
(A-a)PO2 before 14±1 12±1 11±1 ns
after 10±1 ** 13±1 11±2 <0.05
Pallavicini E. 1994 Hackett P. ARRD 1987
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Acetazolamide prophylaxis attenuates increase in cerebal metabolic rate and tissue hypoxia
Wang K
. et al. J Appl P
hysiol 2015 119: 1494 CBF PtiO2
DO2 CMRO2
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Low dose Acetazolamide (2 x125mg) for prophylaxis of AMS
AMS incidence
; 125mg bid ; 375mg bid
Headache incidence
Placebo controlled study in Trekkers ascending to Mt Everest base camp (5350m)
Basynat et al HAMB 2006; 7:17
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Conditions predisposing to the development high altitude disease
Richalet JP et al AJRCCM 2012 185:192
OR for ACZ use: 0.56 (95%CI 0.40-0.80)
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Am J Med 2014 127:1001-1009
Inhaled budesonide (200 mg, twice a day [bid]), oral dexamethasone (4 mg, bid), or placebo (46 in each group).
Travel by care
AMS incidence
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AMS score Systolic Pulmonary Artery Pressure
Berger et al. ERJ 2017 Berger et al. High Alt Med Biol 2017
Inhaled budesonide 200 mg (16) or 800 mg (17) bid, or placebo (16) started 24h prior to ascent
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Berger et al. ERJ 2017
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Rapid descent and bed-rest for the treatment of AMS
2200m SpO2 90%
4500m SpO2 70-75%
Bärtsch P et al. Br Med J 1993, 306: 1098-1101
Changes in AMS score
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Treatment of acute mountain sickness
Excessive fatigue Lassitude
Headache, Nausea
Altered mental status, Ataxia
Acetaminophen resistant headache, Vomiting
Acetazolamide Dexam
ethasone
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British Medical Journal, Volume 294, 30 May 1987
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Effects of acetazolamide and dexamethasone in subjects with AMS
* P < 0.05, ** p < 0.01 Pallavicini E, unpublished
Randomized placebo controlled trial for AMS treatment
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Effects of acetazolamide and dexamethasone on fluid homeostasis
Fluid balance A-aDO2
Acetazolamide Placebo Acetazolamide Dexamethasone
Pallavicini E, unpublished
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Effect of dexamethasone early prophylaxis on inflammation
Change from low to high altitude day 2
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Effect of dexamethasone early prophylaxis on neurohormons
Change from low to high altitude day 2
Adrenomedullin
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Cardiovascular and Fluid Homeostasis
Stimulation Inhibition
water excretion sodium excretion
Glomerular filtration rate
peripheral vascular resistance
Stress & Inflammation Plasma volume ⇑ Myocardial stretch
ANP / BNP Adrenomedullin
Renin Angiotensin II Aldosterone
Vasopressin
Sodium loss
Endothelin 1
Prolactin
Dexamethasone
Vasodilation
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Dexamethasone for the treatment of acute mountain sikness
Mechanism Cytoxines synthesis Cellular Na+-Transport
Effect capillary leak diureses (Kidney tubuli) Water reabsorption (Alv. space)
⇒ Central dysfunction
⇒ PaO2 Dosage 8 - 16 mg per day Therapy of moderate to severe
AMS Ferrazzini Br Med J 1987, 294: 1380-1382
0
1
2
3
4
5
6
7
8 AMS score
Scor
e p
oint
s evening morning
Dexamethasone Placebo
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Combined AMS treatment strategy
Hyperbaric treatment Medical treatment
Dexamethasone 8 mg initially, 4 mg every 6 h.
193 mbar
Keller H-R et al. BMJ 1995, 310: 1232-1235
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High Altitude Pulmonary Edema (HAPE)
Central distributed infiltrates Peripheral distributed infiltrates
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Clinical Presentation of HAPE
Symptoms and Signs • Weakness / Decreased
Exercise Performance • Dyspnoe at Rest, Othopnoe • Cough, Cracels bloody sputum • Chest tightness or congestion HbO2 57%, PaO2 23 mmHg
PaCO2 29 mmHg, pH 7.49 Lake Louise score = 2 points • Tachycarda > 90/min
• Tachypnoe > 25/min • Cyanosis, SpO2 < 70% (4500m) • Lung: Rales or wheezing • Body Temperature > 37.4 °C
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ALVEOLAR EPITHELIUM
ALVEOLUS
ALVEOLAR MACROPHAGE
Alv.T II
INTERSTITIUM
Pathophysiology of high altitude pulmonary edema
Secondary inflammation
IL-1ß TNF-a IL-8
PMN
Pcap
Endothelin-1 Angiotensin Seotonin Norepinephrin
Nitric oxide Prostaglandin
RBC & Prot.
ENDOTHELIUM • Progressiv Str- ess failure
• IL- 6 • Fibrinopeptid A
Alv.T II
Alveolar fluid clearence
ENaC
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Chest ultrasound for monitoring of extravascular lung water in HAPE
Comet-tails artifacts arising from thickened interlobular septa
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Monitoring comet-tails during ascent
Monitoring comet-tails score during ascent to 5130 m (* subjects with HAPE)
Pratali L. et al. C
rit Care M
ed 2010, 38 Epub
O2 saturation
Sub-clinical HAPE?
* HAPE *
* *
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Factors known to be associated with an increased risk of HAPE
Individual susceptibility Open foramen ovale
Congenital atresia/hypoplasia of a pulmonary artery
Pulmonary hypertension at low altitude
Pulmonary embolism
Systemic inflammation decreasing pulmonary capillaries edema formation threshold
Open foramen ovale
Allemann et al JAMA 2006; 296:2964
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Rationale for Prevention and Treatment Based on Pathophysiology
High Altitude Pulmonary edema Inhibition of excessive hypoxic
pulmonary vasoconstriction Vasodilators
Calcium channel blokers Phosphodiestherase 5
inhibitors Improve nitric oxide availability
Phosphodiestherase 5 inhibitors Glucocorticoids
Improve water reabsorption Beta-2-agonists Glucocorticoids
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4
9
7
1
0
2
4
6
8
10
12
Placebo NifedipineN
umbe
r of p
atie
nts
no-HAPE HAPE
Prevention of high altitude pulmonary edema by nifedipine
Systolic pulmonary artery pressure Incidence of HAPE
Bärtsch et al. NEJM 1991 325: 1284-9
64%
10%
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Amylorid sensitive Na+-channel
Na+/ K+ Pump
Non-hemodynamic contribution to HAPE: Improvement of alveolar water clearence
Salmeterol 1
1
Sart
ori,
NEJ
M 3
46:1
631-
36, 2
002 HAPE incidence
n = 37; 2 x 125mg
33 %
74 %
p = 0.02
6/18
14/19
Salmeterol Placebo
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Phosphodiesterase 5-inhibitors to compen-sate decreased nitric oxide availability
Nitric oxide
Sildenfail, Tadalafil
Activation
Nifedipine Dexamethasone
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Possible mechanisms for the dexamethasone effect on gas exchange
Anti-inflammatory effect suppression cytokines synthesis, reduction of the capillary leak enhancement of Na+ transport in renal tubular and alveolar type II cells
water
Na+
Na+
[Na+] Seltzner et al. J Clin Invest 1988, 82:1840
Pulmonary edema
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Dexamethasone increase surfactant protein content in the rat lung
Cont. Dex.
SP-A
SP-B
SP-C Lung mRNA
control dexamethasone
Distribution of rat lung surfactant protein A
pellet
supernatant
Lamellar body
LAVAGE
TISSUE
Youn
g et
al.
Am
J P
hysi
ol 1
991,
260
:L16
1
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Dexamethasone or tadalafil for HAPE prophylaxis during stay at 4559m
Maggiorini et et al. Ann Inter Med 2006 145:497
Double blind randomized controlled trial • Dexamethasone 2 x 8 mg • Tadalafil 2 x 10mg • Placebo
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Dexamethasone or tadalafil for HAPE prophylaxis during stay at 4559m
0 12 24 36 48 0
0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9
1
Per
cent
of p
artic
ipan
ts w
ithou
t HA
PE
Hours at 4559m Participants without HAPE placebo 9 9 8 5 2 tadalafil 10 8 8 7 7 dexamethasone 10 10 10 10 10
Maggiorini et et al. Ann Inter Med 2006 145:497
Double blind randomized controlled trial • Dexamethasone 2 x 8 mg • Tadalafil 2 x 10mg • Placebo
placebo
tadalafil
dexamethasone
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Placebo Tadalafil Dexamethasone 0 1 2 3 4 5 6 7 8 9
10
num
ber o
f sub
ject
s
n = 9 n = 10 n = 10
78%
10%
0%
HAPE p = 0.004
Incidence of High Altitude Pulmonary Edema in Susceptible Subjects
89%
70%
10% AMS only p < 0.001
Maggiorini et et al. Ann Inter Med 2006 145:497
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Effects of Tadalafil and Dexamethasone on arterial oxygenation
Maggiorini et et al. Ann Inter Med 2006 145:497
PaO2 AaDO2
Pla Tada Dex 0
10
20
30
40
50
60
70
PaO
2 (m
mH
g)
p < 0.001
*
*ƒ
Pla Tada Dex 0
5
10
15
20
25
30
AaD
O2
(mm
Hg)
p < 0.001
*
*ƒ
* at least p < 0.05 vs placebo; ƒ vs. tadalfil
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Effects of Tadalafil and Dexamethasone on pulmonary artery pressure
§ mean systolic pulmonary artery pressure Mean with 95% CI * p < 0.01 vs control
Maggiorini et et al. Ann Inter Med 2006 145:497
*
*
§
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Dexamethasone inhibition of hypoxic pulmonary vasoconstriction in the rabbit
Dexamethasone increases nitric oxyde availability in rabbit intrapulmonary arteries leading to vasorelaxation
Murata et al AJRCCM 2004, 170:647
Vasorelaxation eNOS mRNA expression (+) L-NMMA
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Prophylaxis of High Altitude Pulmonary Edema (HAPE)
HAPE HAPE & AMS
Rapid ascent with a short sojourn 1000 m/day + < 5 days above 2500m
Dexamethasone 4-8mg every 12 h
Start 24 h before ascent
Busienesstrip above 2500m
+
Slow ascent 300 m/day
Tadalafil 20 mg every 24 h
Start 24h before ascent
or Nifedipine
CR30-60 every 24 h Start
24h before ascent
Trekking/climbing above 2500m
+ AMS > 2 AMS Symptoms
Azetazolamide 125 mg every 12 h
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Treatment of High Altitude Pulmonary Edema
Non medial treatment • Bed rest • Oxygen / Hyperbaric Bag • Descent Medical treatment options • Nifedipine 3 x 20mg sr • Sildenafil 3 x 25 mg • Tadalafil 1 x 20 mg Medical supportive treatment • Dexamethosone 2 x 8 mg • Acetazolamide 2 x 250 mg
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Pulmonary artery pressure is crucial for the development of HAPE
Oel
z et
al.
Lanc
et 1
989
before
after
Nifedipine
edema
Systolic Ppa
Aa-DO2 gradient
Nifedipine treatment before
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Dexamethasone treatment in HAPE susceptible persons
14 HAPE susceptible persons receiving 2 x 8 mg dexamethasone for AMS at high altitude day 2 after rapid ascent to 4559m
Systolic Ppa (mm
Hg)
AMS-
c sc
ore
2
x H
APE
1
x H
APE
Maggiorini et al. unpublished
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Treatment of High Altitude Pulmonary Edema (HAPE)
HAPE
Nifedipin 20 mg or
Sildenafil 50mg every 8 h
4-6 l/min O2 +
Descent > 1000m
Mild-AMS ≤ 2 AMS Symptoms
+ Mild/Severe AMS > 2 AMS Symptoms
+
Azetazolamide 125 mg every 12 h
Dexamethasone 8 mg loading dose
4 mg every 6 h
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Thank you for your attention
Thank you Margherita researcher and hut keepers team!