Mean PaO 2 24,6 mm Hg (19,1 à 29,5) [normal 90 mmhg asl*] Mean SpO 2 54 % [normal % asl] Mean PaCO 2 13,3 mm Hg [normal 40 mmhg asl]

Transcription

1 Haemoglobin concentration and altitude At 8400 m (blood samples taken at Everest level on climbers, dwelling for more than 60 days between 4500 and 8848m) Mean PaO 2 24,6 mm Hg (19,1 à 29,5) [normal 90 mmhg asl*] Mean SpO 2 54 % [normal % asl] Mean PaCO 2 13,3 mm Hg [normal 40 mmhg asl] Mean ph 7,53 [normal 7,35-7,45 asl] Haemoglobin concentration 19,3 g/dl [normal g/dl asl] Mean blood bicarbonate 10,8 mmol/l [normal asl] Again, we are no more in normal range, even after acclimatization Hypoxia and cardiac load Qc is increased from the first day of the stay to maintain TO 2 and it slowly decreases in the next two weeks. There are specific reasons related to altitude for a further increase in cardiac work: increase of right ventricle afterload: PH, RBC (blood viscosity) increase of left ventricle afterload: vasoconstriction related to cold In heathly subjects, coronary perfusion is well preserved (hypoxia adenosine as the result of ATP degradation; adenosine is the main dilator in coronary vessels). Cardiac patients are restrained under 3000m (therefore, they can usually take a plane). Arterial pressure (AP) during a dynamic exercise Systolic AP Diastolic AP Pulmonary artery pressure (PAP) during a dynamic exercise Systolic PAP At sea level Systemic resistance (dyne.cm -5.s) SR >> Qc Diastolic PAP Mean AP Mean PAP Pulmonary resistance (dyne.cm -5.s) Very low During exercise, blood flow in coronary and muscles and in liver, kidney, GT, resting muscles, skin without major changes in global brain flow When pressure at the entry of lung circulation increases ( Qc) : 1) Pulmonary vessels in use are stretched 2) Unused vessels are recruited (mostly from upper areas of lungs when vertical) Recruitment Stretch Hypoxic vasoconstriction as good thing (pneumonia, fetus, homogeneizing the lung) Perfusion of hypoxic zones : Venous blood remains venous and contaminates arterial blood, leading to a massive fall in PaO 2 (ARDS and severe pneumonia, also the fetus whose lung is full of amniotic liquid, and in general reduces V/P inequality ) Locally hypoxic alveola AIR Normoxia HYPOXIC VASOCONSTRICTION limits these changes In altitude this reflex has no good quality: all the lung is hypoxic and there is nothing that our body can do to reduce that. PH is a burden for right ventricle and a contributing factor for pulmonary edema Hypoxic vasoconstriction Derives blood away fron non-ventilated area 1

2 PAP increase and hypoxia: the limits of acclimatization RBC Hb increase and hypoxia: the limits of acclimatization Rest Lowlanders (Northern Americans) Strong hypoxic vasoconstriction (V+) Less V+ When Hb blood concentration goes over about 200 g/l, the increase in RBC is such that the increase in blood viscosity greatly increases systemic and pulmonary resistances. The increase in RV afterload limits cardiac output during exercise, canceling the advantage of Hb increase in O 2 transport. Almost no V+ Tibetans Qc (TO 2 = Qc X CaO 2 ) It would also lead to subsequent cardiac failure. Tissue oxygenation in hypoxia 23 DHPG Oxygen dissociation curve is LEFT-SHIFTED under the influence of cold, alcalosis and 2-3 DPHG -increased by hypoxia) This shift favors O 2 loading at the lung level when diffusion is limited This shift is less in highlanders who have a greater diffusion capacity P tiss O 2 falls fast away from the capillary : Capillary density under hypoxia increases in the 1000 to 3000m range (maximal increase at about 2000m), in relation to VEGF increase. The changes are mostly seen when people exercise However, above 4000 m VEGF falls and muscular fibers became atrophic, before severe wasting above 6000m. Above 6000m, in lowlanders, muscle fiber oxygenation is reduced, glycolytic enzymes are increased whereas oxidative ones are reduced Tissue oxygenation in hypoxia Myoglobin, its role Stocks O 2 in tissue and allows to maximize the gradient of O 2 partial pressures between mitochondria and capillaries. Interestingly, there is much more MyoHb in highlanders whereas there is little if any MyoHb increase during long stay in lowlander. Interactions between myoglobin, O 2 and NO When myohbo 2 is available, there is less NO, less vasodilation and less limitation in mitochondrion activity (O 2 is available, so use it). When only myohb, NO is available as a vasodilator and limits mitochondrion activity. (no more O 2, stop consuming it and bring more arterial blood). HYPOXIA Acclimatization Acute HR HV chronic Hb CO 2 VR Adaptation A life Generation HVR PHPR Capillary density (< 2000 m) minutes days years Hypoventilation (Log scale) 2

3 Acid-base balance in exercise under normoxia Muscular ph regulation * Under normoxia muscles ph: - increases during phosphocreatine hydrolysis to supply ATP (ph will decrease when ATP is regenerated) - decreases through H + supply resulting from aerobic glycolysis (ATP generation) with La supply by 1) the glycogen shunt** 2) the excess of glycolytic pyruvate supply to the Krebs cycle leading to La accumulation. PASSIVE FLUXES Muscular cell ACTIVE FLUXES Intense exercise Moderate exercise ** glycogen phosphorylase promotes rapid transformation of glucose-6- phosphate to La and H + For a lasting and heavy exercise, muscles experiment acidosis. This acidosis is even greater immediately after the exercise. * As protons released from the muscles go to blood, to maintain blood ph constant, there is a high buffer power. The main components are bicarbonates (HCO 3 ), Hb and other plasma proteins, and phosphates ions (2-3 DHPG, Pi). The constant acid load resulting from metabolism and H + passive influx are compensated by -H + output (Na + /H + antiport, La/H + symport moves La H+ depending on a membrane protein Mono Carboxylate Transport MCT with their various isoforms MCT1 -uptake- and MCT4 -efflux) Acid-base balance in muscle exercising under hypoxia The muscle is -the main producer of La H +, -the main consumer of La. The maintenance of muscular ph in the normal range depends on concentrations of three main buffers : -Pi, - Bicarbonates, - Proteins. It is mainly proteins which are increased by training. Acid-base balance in muscle under hypoxia Muscle ph under hypoxia in acclimatized lowlanders under 6000m is the same than in normoxia at rest (7.15) and slightly less for the same power (6.7 versus 6.6)! Above 6000m, muscle ph further decreases, both at rest and exercise. Hypoxia modifies in a complex way MCT activity. Non-bicarbonate blood buffers increase (Hb, 2-3DHPG, more than compensating the fall in bicarbonate). Non-bicarbonate muscles buffers increase at exercise at moderate altitude and decrease during a long stay above 6000 m. A long stay at high altitude for lowlanders leads to catabolism of proteins which decrease their role as a muscle buffer. For Himalayan people, data on muscle wasting are lacking At a certain power, blood La rises, faster in subjects trained in high intensity short duration exercise than in the ones trained in long duration ). Under heavy endurance exercise, both H + and La are liberated in blood. Cell acidosis decreases contractile strength and Ca ++ reuptake becomes difficult La rise in normoxic exercise which leads to further increase and cell toxicity La paradox : acute and chronic hypoxia (1/5) La max rise at maximal exercise is about the same in the lowlander under ACUTE hypoxia or in normoxia. However After 4 weeks stay - ( m range), ACCLIMATIZATION takes place: VO 2max which was low, increases. Nevertheless La max decreases when compared to previous values! One would predict the opposite as the power is higher and the anerobic metabolism is recruited. This is what was named La paradox 3

4 La paradox : acute and chronic hypoxia (2/5) La paradox disappears when back to normoxia (3/5) La max is less above 4500 m both in acclimatized lowlander and in Himalayan people living there All the groups exercising in normoxia 1) In lowlander, normal La rise again 2) in Himalayan people exercising at sea level La rise appears La paradox disappears if lowlanders stay above >5500m (4/5) Possible interpretation of La paradox (5/5) La paradox = TRANSIENT oxidative metabolism et anaerobic glycolysis. When La paradox disappears, muscular wasting begins (reduction in mitochondria volume, lipofuscine, ROS). At the same altitude range, no muscular wasting is seen in Sherpas, even during long stay, and La paradox remains. HIF1 signaling for EPO, VGEF, cytokines et HSP and oxidative enzymes. HIF1 protects tissue from hypoxia, but this process has limits. The disappearance of La paradox is a marker of the limits of acclimatization. Diseases caused by altitude Acute disease : Acute and subacute mountain sickness High-altitude pulmonary edema High-altitude cerebral edema Chronic disease : Chronic mountain sickness: Monge s disease (seen in lowlanders living at high altitude, in Indians from Andes, in Chinese in Tibet, but not in Himalayan people) Acute and subacute mountain sickness (AMS) Headache, gastrointestinal symptoms, fatigue, dizziness, difficulty sleeping, change in mental status, ataxia, peripheral edema are the main ponts to score (Lake Louise consensus) AMS begins from 24 to 48 h (if you stay 1 or 2 h, usually nothing cf. Pikes Peak 4300 m). AMS is seen from 2500 m. 30 % are more or less sick above 3000 m (the faster you rise, the higher is the risk of being sick) 4

5 Acute and subacute mountain sickness (AMS) Possible mechanisms underling AMS The degree of hypoxic ventilatory response is not a predictor of AMS. In fact the sole solid predictor is the previous experience of AMS! SRA ADH ANP Na H 2 O retention AMS usually disappears in 3-4 days. However, it can lead to a more severe condition as high-altitude pulmonary edema (HAPE) or highaltitude cerebral edema (HACE) There is a minimal degree of cerebral edema (ANF, SRA, increase in EC fluid). Hypoxia cerebral capillary permeability (HIF1 : cytokines, inos, VEFG, ANP) AMS Could lead to HACE and HAPE AMS Prophylaxis : * Slow ascent below 3000 m (each night should be spent no more than 300 m above the last with a rest day every three days). * Acetazolamide (Diamox) (blocks the conversion of CO 2 to carbonic acid, favors intra cellular acidosis leading to respiratory stimulation, favors renal elimination of bicarbonate forcing acclimatization). Begin taking it 2 days before hypoxia (750 to 500 mg/dy) and continue during all stay *Spironolactone and steroids are often associated AMS treatment First rest as rest alone often relieves the symptoms of ASMS. Give steroids. If no improvement in 2 days or rapid aggravation = get down, even 300 m may be enough. O 2 temporarily masks symptoms and blocks acclimatization High altitude pulmonary edema (HAPE) Begins either after unresolved AMS (50 %) or as the first symptom of altitude intolerance (50%). One case of HAPE 18 h after getting down Cough, increasing and dyspnea first on exercise, then at rest One can die from HAPE without treatment of with a late treatment Hypoxia Possible mechanisms underling HAPE PAP leading to stress failure of pulmonary capillary and high protein edema. Negative effect of MECHANICAL THEORY Secondary inflammation (BAL) (cytokines, inos ) INFLAMMATION THEORY Decrease in Na + /K + /ATPase which is a defender of dry alveolar space (positive effect of ß agonist) NEW THEORY HAPE FO opens 5

6 HAPE treatment As fast as possible treat and get the patient down. HAPE prophylaxis Slow ascent below 3000 m (each night should be spent no more than 300 m above the last with a rest day every three days). Diamox - O 2 if available (10l/min, when better 2-4l/min) - Nifedipine (calcium channel blocker, thus a potent vasodilator) - Expiratory positive airway pressure mask Portable hyperbaric chamber (Gamow or Certec bags)??? Steroids and diuretics? Low efficiency Salbutamol inhalation as a protective drug has reduced its frequency from 50 % in one study. Sidenafil (Viagra ) also decreases PAP in one study Portable hyperbaric chamber? High altitude cerebral edema (HACE) Either following unresolved ASMS or the first symptom of altitude intolerance. Headache, gastrointestinal symptoms, hallucinations, clouding of the consciousness, blurring vision, troubles visions (retinal haemorrhage) Capillary permeability resulting from, SRA and FAN (Na and water retention). O 2, getting down, steroids, portable hyperbaric chamber. But the patient is isolated (difficulty to assess his condition, to inject drugs, rebound effect when out) and fatigue for the all group when the situation lasts because continuous pumping above 5000 m is quite a heavy work! Retinal haemorrhage can be seen alone (resolving) Temporary cortical blindness has been reported: lasting 1 to 24 h, relieved by O 2 breathing, due to hypoxia) Chronic moutain sickness: Monge s disease Andes+ (discovered in Peru 1925), Himalaya ± 0 Headache, dizziness, somnolence, fatigue, difficulty in concentration, low mental acuity, depression, hallucination, poor exercise tolerance. When the patient gets down, all these symptoms disappear and only reappear on return to altitude Large increase in RBC count and Hb concentration (280 g/l!!) and very high blood viscosity ; both are hypoxia-related. A classic textbook High Altitude Medicine and Physiology Michael P. Ward, James S. Milledge, John B. West Arnold London (2000) ( AP et PAP): Thrombosis, chronic cerebral hypoxia, reduced lung function (V/P, diffusion, shunt). Venesection, Diamox 6