Presentation is loading. Please wait.

Presentation is loading. Please wait.

EXTREME PHYSIOLOGY HIGH ALTITUDE PULMONARY EDEMA Abundio Balgos, M.D., MHA, FPCP, FPCCP, FCCP Agatep Tolete Professor of Medicine Associate Dean for Planning.

Similar presentations


Presentation on theme: "EXTREME PHYSIOLOGY HIGH ALTITUDE PULMONARY EDEMA Abundio Balgos, M.D., MHA, FPCP, FPCCP, FCCP Agatep Tolete Professor of Medicine Associate Dean for Planning."— Presentation transcript:

1 EXTREME PHYSIOLOGY HIGH ALTITUDE PULMONARY EDEMA Abundio Balgos, M.D., MHA, FPCP, FPCCP, FCCP Agatep Tolete Professor of Medicine Associate Dean for Planning and Research U.P. College of Medicine

2 Disclosures Currently a Professor at the College of Medicine, University of the Philippines, Manila Active Pulmonary Consultant at Manila Doctors Hospital and Associate Active Consultant at Makati Medical Center Has done studies, and given lectures in relation to these studies, for Astra Zeneca, Glaxo Smith Kline, Eli Lilly, Pfizer, United Laboratories, Pharmacia, Pfizer, Bayer, and Otsuka; these have no bearing on the lecture on High Altitude Diseases

3 High altitude data: 140M people reside at altitudes >2500m There are telescopes at >5000m and mines at >4500m 30 to 50,000 workers in the Tibet railroad project worked at >4000m Skiers and mountain trekkers go to 3000m mostly, some to >8000m West, JB. Annals Intern Med, 2004, 141: DO WE NEED TO KNOW HIGH ALTITUDE DISEASE?

4 Up to 2004, Himalayan database showed that: Mt. Everest summit was reached 2251 times 130 of these ascents were without supplemental oxygen Can anyone climb Mt. Everest?

5 Who really was the first Filipino to reach the summit of Mt. Everest? Leo Oracion Erwin Emata Romy Garduce Dale Abenojar

6 HOW HIGH IS HIGH-ALTITUDE ? High altitude: m above sea level Very high altitude: m Extreme altitude: above 5000m For sea level visitors, m = highest acceptable level for permanent habitation For high altitude residents, m = highest so far recorded Tibetan plateau & Himalayan valleys (8848m) Andes (6962m) Ethiopian highlands (4620m)

7

8 2085PalawanMt. Mantaling 2117PanayMt. Madiaas 2430NegrosKanlaon Mountain 2938MindanaoMt. Katanglad 2462LuzonMayon Volcano 2582MindoroMt. Halcon 2922LuzonMt. Pulog 2954mMindanaoMt. Apo

9 LECTURE OUTLINE Review of basic physiological principles of respiration as they relate to changes in pressure and temperature Animal and human adaptations to high altitude What happens when acclimatization fails ? –Acute mountain sickness –High altitude pulmonary edema –High altitude cerebral edema

10 External Respiration

11 Atmospheric composition at sea level GAS PERCENT NITROGEN OXYGEN ARGON 0.94 CARBON DIOXIDE 0.03 HYDROGEN 0.01 NEON HELIUM

12 Atmospheric Pressure declines with altitude Sea level: 1 atm = 14.7 lbs/inch 2 (psi) 18,000 ft (5,486 m): 0.5 atm = 7.35 psi

13 2954 m Mt. Apo Pressure reduced to 1/2 atm 1 atm increase every ~10 m 0.1 atm reduction every 1km Sea Level = 1 atm 13 atm 370 atm m average depth of oceans 1086 atm m Mariana Trench -130 m m Mount Everest m Human Settlement, Tibet Reduction in Pressure And O2 Increase in Pressure And Gas Solubility Atmosphere Hydrosphere

14 Pressure differences are enormous, leading to differences in oxygen supply for air-breathers Mt. Apo Baguio City

15 Adaptations to high altitude High altitude mammals: More pigment in blood High affinity hemoglobin Birds: (1) Cross-current flow of air and blood allowing higher O 2 concentration in blood than in exhaled air (2) Tolerate low CO 2 in blood (Alkalosis) (3) Normal blood flow to the brain at low blood PCO 2 (4) Total respiratory volume is 3X that of mammals

16 Evolution of hemoglobin function Highland Camelids (llama, vicuña, alpaca) display lower P 50 (higher affinity) than lowland Asian/African camels Amino acid substitutions in - globin chains which reduce the effect of DPG binding A small number of substitutions are sufficient to adapt the functional properties of hemoglobin to severely hypoxic conditions

17 Adaptation vs Acclimation/Acclimatization 1) Short Term Acclimation Mountain climbers who are able to maintain normal blood pH at low oxygen 2) Developmental Acclimation A person reared at high altitude: larger lung volume Higher concentration of red blood cells 3) Adaptation Llamas: Blood with high Oxygen affinities

18 High Altitude: Humans Developmental Acclimation (Mountain People) Larger lung volumes 40% higher ventilation rate in populations at 4500m ( maladapted hyperventilation) Increase number of blood cells (5 million/mm 3 --> 8 million/mm 3 at 4000m) Increase myoglobin concentration in muscles Effect on Enzymatic pathways not understood Increase in number of muscle capillaries and mitochondria Whether Adaptive differences occur in Humans is not known

19 High Altitude: Humans Highest permanent settlement: 5000m mining camp in Andes RESPONSE TO LOW O 2 : Hyperventilation leading to low PCO 2 Chronic Hypoxia

20 High Altitude: Humans Acclimation (or Acclimatization) Change in response of respiratory center (in hypothalamus) Adjust bicarbonate concentration in blood to maintain normal blood pH at low PO 2 (and low PCO 2 that arises from hyperventilation)

21 Process by which people gradually adjust to high altitude Determines survival and performance at high altitude Series of physiological changes O 2 delivery hypoxic tolerance +++ Acclimatization depends on severity of the high-altitude hypoxic stress rate of onset of the hypoxia individuals physiological response to hypoxia ACCLIMATIZATION

22 High Altitude: Humans Hyperventilation (negative feedback)Hyperventilation (negative feedback) (1) In response to low O 2, ventilation increases (2) But then this reduces PCO 2 (3) pH increases, reducing normal stimulation in the respiratory center (3) pH increases, reducing normal stimulation in the respiratory center (4) Reduces ventilation (5) Decrease oxygen supply (6) More increased ventilation to gain O 2 Hypoxia: Brain damage after 4-6 minutes of oxygen deprivationHypoxia: Brain damage after 4-6 minutes of oxygen deprivation

23 Heart and Pulmonary Circulation at High Altitude Penaloza, D and vier Arias-Stella J. Circulation. 2007;115: )

24 Hypoxic ventilatory response = VE Starts within the 1 st few hours of exposure 1500m Mechanism VENTILATORY ACCLIMATIZATION Ascent to altitude Hypoxia Carotid body stimulation Respiratory centres stimulation Increased ventilation Improved hypoxia Decreased PCO 2 CO 2 + H 2 O H 2 CO 3 HCO H +

25 alkaline bicarbonate excretion in the urine but slow process ! Progressive increase in the sensitivity of the carotid bodies After several hr to days at altitude (interval of ventilatory acclimatization): cerebrospinal fluid pH adjustment to the respiratory alkalosis new steady state ADJUSMENT OF RESPIRATORY ALKALOSIS

26 VENTILATORY RESPONSE TO EXERCISE Varies with hypoxia ventilatory response (HVR) at rest at sea level –Larger ventilatory response climbing performance –but, at extreme altitude, larger work of breathing altitude trade-off Schoene et al., 1984

27 LUNG DIFFUSION Definition Process by which O 2 moves from the alveolar gas into the pulmonary capillary blood, and CO 2 moves in the reverse direction High altitude O 2 diffusion, because of –a lower driving pressure for O 2 from the air to the blood –a lower affinity of Hb for O 2 on the steep portion of the O 2 /Hb curve and inadequate time for equilibration

28 West et al., 1983 CONSEQUENCE O 2 DIFFUSION arterial O 2 saturation Wagner et al, Mt. Everest II project,1995

29 Varies from zero to infinity Zero : perfusion but no ventilation –O 2 and CO 2 tensions in arterial blood, equal those of mixed venous blood because there is no gas exchange in the capillaries Infinity: ventilation but no perfusion –no modification of inspired air takes place due to over- ventilation or under-perfusion VA/Q HETEROGENEITY

30 At high altitude –interstitial edema heterogeneity +++ VA/Q HETEROGENEITY O2O2 At rest - Inhaled air is not evenly distributed to alveoli - Composition of gases is not uniform throughout lungs - Different areas of the lungs have different perfusion - Differences are less in recumbent position

31 Penaloza, D and vier Arias-Stella J. Circulation. 2007;115: )

32 Hct Range Hct Midpoint Log SD Perfusion Mean Perfusion Log SD Ventilation Mean Ventilation , MIGET evaluation of Ventilation-perfusion relationships during induced polycythemia (with no pulmonary hypertension) Balgos A, Willford D, West JB. J Appl Physiol, 65(4): , 1988

33

34 Maximal oxygen consumption at high altitude 85% of sea level values, at 3000m; 60% at 5000m, and only 20% at 8000m Ascribed to reduction in mitochondrial PO2 Could also be due to central inhibition from brain Most likely not due to pulmonary hypertension Elite mountaineers tend to have an insertion variant of angiotensin-converting enzyme gene West, JB. Annals Intern Med, 2004, 141:

35 Effects on Mental performance Most people working at >4000m experience increased arithmetic error, reduced attention span, and increased mental fatigue Visual sensitivity (night vision) decreased at 2000m, and up to 50% at 5000m Molecular and cellular mechanisms of these effects of hypoxia are poorly understood Suggested mechanisms: altered ion homeostasis, changes in calcium metabolism, alterations in neurotransmitter metab., and impaired synapse function West, JB. Annals Intern Med, 2004, 141:

36 Effects on Sleep Sleep impairment common and most distressing: frequent awakenings, unpleasant dreams, do not feel refreshed on waking up in the morning Periodic breathing,which occurs at >4000m is most likely an important causative factor Possible reasons for periodic breathing: instability of of control system for hypoxic drive, or response to CO2, as well as low levels of PaO2 after apneic episodes West, JB. Annals Intern Med, 2004, 141:

37 WHEN ACCLIMATIZATION FAILS Altitude syndromes –Acute mountain sickness (AMS): the least-threatening and most common –High altitude pulmonary edema –High altitude cerebral edema All these syndromes have –several features in common –respond to descent or oxygen potentially lethal form of AMS

38 ACUTE MOUNTAIN SICKNESS Major symptoms –Headache –Fatigue –Dizziness –Anorexia –Dyspnea (but tricky!) Incidence and severity depend on –Rate of ascent –Altitude attained –Length of time at altitude –Degree of physical exertion –Individuals physiological susceptibility Treatment hardly needed Only a problem if progression of symptoms to those of –HAPE –HACE

39 HIGH ALTITUDE PULMONARY EDEMA (HAPE) Noticed only after 24-48hr and occurs after the 2 nd night Occurs in otherwise healthy people without known cardiac or pulmonary disease –1:50 climbers on McKinley succumb to HAPE (Hackett et al., 1990) Occurs when people go rapidly to high altitude Extravasation of fluid from the intra- to extravascular space in the lung Noticed only after 24-48hr and occurs after the 2 nd night Occurs in otherwise healthy people without known cardiac or pulmonary disease –1:50 climbers on McKinley succumb to HAPE (Hackett et al., 1990) Occurs when people go rapidly to high altitude Extravasation of fluid from the intra- to extravascular space in the lung

40 WHY DOES HAPE OCCUR ? Hypothesis 1. Pulmonary hypertension Strong relationship between the development of HAPE in people with –Mild pulmonary hypertension at rest –Accentuated pulmonary vascular response to hypoxia or exercise But pulmonary hypertension alone is not enough to result in HAPE (Sartori et al., 2002) There is strong evidence that HAPE is due to patchy capillary damage due to pulmonary hypertension (West JB, 2004)

41 WHY DOES HAPE OCCUR ? Hypothesis 2. Pulmonary endothelium barrier fragility –Pulmonary endothelium barrier susceptible to Mechanical stress Stretching of the endothelium gaps passage of proteins and red blood cells Inflammation Mediators release permeability gaps passage of proteins, red blood cells and inflammatory mediators Questions: –inflammation = 1 st culprit –High pressure alone enough to result in extra vascular leak ?

42 INFLAMMATION IN HAPE ? Schoene et al., 1986, 1998 –[Leukotrienes] (marker of inflammation) very high in BAL in subjects acutely ill with HAPE But is inflammation present at the start or as a result of HAPE ? Swenson et al., 2002 –RBC and proteins present in BAL in people at onset of HAPE –But no inflammatory markers present Inflammation probably not the causative factor Swenson et al., 2002

43 HYPOXIC PULMONARY VASOCONSTRICTION The stress failure theory (West et Mathieu-Costello, 1998, 99) Alveolar hypoxia capillary pressure (some capillaries) Hypoxic pulmonary vasoconstriction (uneven) Damage to capillary wall (stress failure) EDEMA Exposed basement membrane Inflammatory mediators VA/Q heterogeneity West, JB. Annals Intern Med, 2004, 141:

44 EXERCISE-INDUCED HYPOXEMIA Alveolar hypoxia capillary pressure (some capillaries) Hypoxic pulmonary vasoconstriction (uneven) Damage to capillary wall (stress failure) EDEMA Exposed basement membrane Inflammatory mediators VA/Q heterogeneity EXERCISE +/- MORE HYPOXEMIA O2O2 results in about ½ endurance athletes (Powers et al., 1988)

45 INTEGRITY OF PULMONARY BLOOD-GAS BARRIER IN ATHLETES Hopkins et al., 1997 –BAL in 6 athletes after a 7min exercise at maximal intensity –Post exercise: RBC Total protein Albumin Leukotrienes B4 Hopkins et al., 1998 –1h at 70% VO 2 max no signs of alteration Impairment of the integrity of blood-gas barrier only at extreme level of exercise in elite athletes > control subjects at rest

46 West et al., 1995 Costello et al., 1992 Full break of the blood-gas barrier Circular break of the epithelium Red cell moving out of the capillary lumen (c) into an alveolus (a)

47 WHY DOES HAPE OCCUR ? Hypothesis 3. Perturbation of alveolar fluid clearance Role of fluid in extravascular space depends on: –Its accumulation –Efficiency of its rate of clearance Hypoxia Na,K-ATPase activity (Dada et al., 2003)

48 PREVENTION OF HAPE Don't climb at high altitude!!!! Undergo hypoxic ventilation test to determine natural fitness for high altitude If not fit, undergo training, and plan for slow ascent (At altitudes above 3000 m individuals should climb no more than 300 m per day with a rest day every third day) Avoid strenuous physical exertion Anyone suffering symptoms of acute mountain sickness should stop, and if symptoms do not resolve within 24 hours descend at least 500 m.

49 TREATMENT OF HAPE Get the patient down in lower altitude as fast and as low as possible Give O 2 or hyperbaria Apply expiratory positive airways pressure –With a respiratory valve device –Or by pursed lips breathing Treat like any other case of pulmonary edema; in some cases, antibiotics may be needed

50 SPECIFIC TREATMENT OF HAPE Acetazolamide, oral mg 2x/day Dexamethasone, oral. I.M. or I.V. 2 mg q 6hrs or 4 mg q 12 hrs. Nifedipine, oral mg long-acting, q 12 hrs. Tadalafil oral 50 mg. 2x/day Sildenafil 50 mg q 8 hrs Salmeterol inhaled 125mg 2x/day

51 MedicationRenal Insufficiency Hepatic Insufficiency Pregnancy Other Issues Acetazolamide Avoid if GFR <10 mL/min, metab acidosis, hypoK, hypercalcemia, & hyperphosphatemia Contraindicated Category C Avoid if w/ concurrent long- term aspirin; cuation with sulfa allergy; avoid concurrent K- wasting diuretics and ophthalmjic CAI Dexamethasone No C.I.; No dose adjustments Category C May increase FBS in diabetics; avoid in PUD or GO-bleed risk patients Nifedipine No C.I.; No dose adjustments Best to avoid; if use necessary, 10 mg B.I.D. Category C Caution PUD or GO-bleed risk or gastroesoph varices patients Tadalafil 5mg if GFR mL/min. Max 10 mg; <5 if GFR < 30mL/min. Child's Class A & B = 10mg/dL; Child's class C= don't use Category B I ncr. Risk of GERD; caution with other meds affecting cP450; avoid concurrent nitrates and B-blockers Sildenafil Same dose adj as Tadalafil Decrease dose; start with 25 mg; avoid use if with g-e varices Category B I ncr. Risk of GERD; caution with other meds affecting cP450; avoid concurrent nitrates and B-blockers Salmeterol N o C.I.; No dose adjustments Insufficient data; best to avoid Category C Potential for adverse reaction in pts w/ CAD prone to arrhythmia; avoid concurrent beta-blockers, monoamine oxidase inhibitors, or tricyclic antidepressants Luks and Swenson, Chest, 2008; 133:

52 Medication Malaria Traveler's Diarrhea Acetazolamide No known interactions with prophylaxis med, but could increase serum quinine concentration No interactions with fluroquinolones or macrolides; Dexamethasone No known interactions with prophylaxis or treatment meds Potential increased risk of tendon injury Nifedipine No reported interactions with prophylaxis or treatment med, except mefloquine Avoid clarithromycin; safe to use azithromycin and fluroquinolones Tadalafil No reported interactions with prophylaxis or treatment med, except mefloquine Avoid clarithromycin; safe to use azithromycin and fluroquinolones Sildenafil No reported interactions with prophylaxis or treatment med, except mefloquine Avoid clarithromycin; safe to use azithromycin and fluroquinolones Salmeterol Avoid chloroquine due to increased risk of QT- interval prolongation and ventricular arrhythmia. Other agents safe to use Avoid clarithromycin; safe to use azithromycin and fluroquinolones Luks and Swenson, Chest, 2008; 133:

53 KEY POINTS High altitude = stressful environment for the lungs –At extreme altitudes : lung = primary and essential organ for human function and survival HAPE = potentially lethal form of AMS –Extravasation of fluid from the intra- to extravascular space in the lung –Main mechanism involved: pulmonary hypoxic vasoconstriction Capillary stress failure Exercise-induced hypoxemia at sea level shows a similar pattern

54 Respiration is directly tied to metabolism, and physical and physiologic principles High Pressure and Altitude pose problems for Respiration, which reach the limits of normal physiology Different animals, including man, respond to high altitude through adaptation and/or acclimatization; Gene regulation of Hemoglobin evolves more quickly than structural changes Acute ascent to high altitude poses clinical problems that could lead to various forms of acute mountain sickness (AMS) which, like HAPE, may be fatal Prevention and early recognition of symptoms of HAPE important, for prompt treatmentSummary

55 Best treatment is prevention Specific treatment modalities helpful, but not always successful Best treatment is descent from high altitude. Other supportive treatment similar to any capillary leak pulmonary edema is often necessarySummary

56 RECOMMENDED REFERENCES BOOK Ward et al. High altitude medicine and physiology. 3 rd edition. Arnold ARTICLES Hopkins et al. Intense exercise impairs the integrity of the pulmonary blood-gas barrier in elite athletes. Am J Respir Crit Care Med. 1997;155(3): West JB et al. Pathogenesis of high-altitude pulmonary oedema: direct evidence of stress failure of pulmonary capillaries. Eur Respir J. 1995;8(4): Schoene. Unraveling the mechanism of high altitude pulmonary edema. High Alt Med Biol. 2004;5(2): West, JB. The Physiologic Basis of High Altitude Diseases. Annals Intern Med, 2004, 141: Luks and Swenson, Chest, 2008; 133: Martin, et al. Variattion in human performance in the hypoxi mountain environment. Exp Physiol, 2010; 953:


Download ppt "EXTREME PHYSIOLOGY HIGH ALTITUDE PULMONARY EDEMA Abundio Balgos, M.D., MHA, FPCP, FPCCP, FCCP Agatep Tolete Professor of Medicine Associate Dean for Planning."

Similar presentations


Ads by Google