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ZS_IS2 _hints

ZS_IS2 _hints. Q1. Co je hypoxie organismu a jaké znáte příčiny hypoxie? Jak na hypoxii reagují buňky a jak organismus?. HYPOX IA. Hypoxia is the lack of oxygene in the whole organism or in selected tissues. Hypoxia results in cellular and tissue damage due to the lack of ATP in cells.

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ZS_IS2 _hints

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  1. ZS_IS2_hints

  2. Q1 Co je hypoxie organismu a jaké znáte příčiny hypoxie? Jak na hypoxii reagují buňky a jak organismus?

  3. HYPOXIA • Hypoxia is the lack of oxygene in the whole organism or in selected tissues. • Hypoxia results in cellular and tissue damage due to the lack of ATP in cells.

  4. HYPOXIA Hypoxia can by fulminant(sudden interrupton of blood circulation – venticular embolia, suffocation), or chronic. Hypoxia can be systemic(any lung disorders,anemia, CO intoxication, chronic heart failure) andlocal (thrombosis, trauma, tumor).

  5. COMPENSATION OF HYPOXIA ON THE CELLULAR LEVEL Cellular sensor: hypoxia inucible factor (HIF) COMPENSATION: Induction of anaerobic glycolysis and cellular glucose uptake, ↑ lactate (metabolic acidosis) Activation of angiogenesis ↑ EPO (erythropoietin) Activation of proteins sensing the tissue damage (p53), ↑ DNA and protein repair molecules

  6. HIF IS A TRANSCRIPTION FACTOR • hypoxia-inducible factor (HIF)-1a • proline hydroxylases (PHD1, 2 and 3) • 2-oxoglutarate (2-OG) • von Hippel–Lindau (VHL) • Acetylation of HIF-1a (OAc) • hypoxia-response elements (HREs) • transcriptional co-activators such as p300/CBP

  7. CLINICAL SIGNS OF HYPOXIA • Increased ventilation • Increased heart rate • Cyanosis, pallor • Fatigue, weakness, vertig, giddiness • Decreased mental performance • Uncounsciousness, coma • ↑ hematokrit (hypoxic hypoxia, take days)

  8. For oxygen transport to tissues an organism needs adequate: Pulmonary ventilation Diffusion of O2 through the alveolo-capillary membrane into blood The transport of O2 into capillaries Diffusion of O2 from capillaries to cells Diffusion of O2through cytosol to mitochondria TISSUE OXYGEN SUPPLY

  9. Hypoxia in altitude sickness Bone marrow erytropoiesis erythropoetin pO2 kidneys + O2 CO2 O2 CO2 Respiratory hypoxia (hypoxic) Circulatory hypoxia (ischemic) Anemic hypoxia Histotoxic hypoxia Sugars Lipids Proteins H2O mitochondria cell mitochondria

  10. CLASSIFICATION OF HYPOXIA • HYPOXIC HYPOXIA: decrease of paO2 (the lack of oxygen in the environment – altitude sickness, disturbances of ventilation and perfusion, septal defects of the heart) • ANEMIC HYPOXIA (anemia,hemoglobinopathia) • CIRCULATORY HYPOXIA (↓blood pressure, Arterio-Venous shunts, bleeding, tumour, thrombosis and embolia) • HISTIOTOXIC HYPOXIA (cyanide poisioning)

  11. COMPENSATION OF HYPOXIA ↑VENTILATION ↑HEART RATE ↑2,3 DPG (diphosphoglycerate) in erythrocytes, Hb releases oxygen more avidly ↑EPO, increase of erythrocytes and hemoglobin

  12. HYPOXIA AND LABORATORY PARAMETERS • Hematocrit, hemoglobin, red blood cell values • pO2, pCO2 a ABB (arterial blood), hemoglobin oxygen saturation – pulse oxymetry • Blood pressure, heart rate, TK, pulz, ergometry, blood lactate

  13. Q2 Jaké znáte mechanismy vzniku metabolické acidózy? Jak se projeví na změnách aniontového okénka (Anion Gap)?

  14. Causes of metabolic acidosis (4) diarhea + TA+NH4 (3)HCO3- loss Failure of bicarbonate reapsorption (1) increased metabolic production of strong acids Bicarbonate reabsorption (2) Failure of H+ excretion H+ excretion CO2 HCO3- H2CO3 H+ retention H+ depletion H+ H2O HBuf A- Buf -

  15. Anion gap • The unmeasured anions include anionic proteins, (e.g., albumin), phosphate, sulfate, and organic anions. • An increase in the AG • most often due to an increase in unmeasured anions • less commonly due to a decrease in unmeasured cations (calcium, magnesium, potassium). • the AG may increase with an increase in anionic albumin (increased albumin concentration or alkalemia - which alters albumin charge). • A decrease in the AG can be due to • an increase in unmeasured cations; • the addition to the blood of abnormal cations, such as lithium (lithium intoxication) • increase in cationic immunoglobulins (plasma cell dyscrasias) • reduction in the major plasma anion albumin concentration (nephrotic syndrome) • decrease in the effective anionic charge on albumin by acidosis • hyperviscosity and severe hyperlipidemia, which can lead to an underestimation of sodium and chloride concentrations. • A fall in serum albumin by 10 g/L from the normal value (45 g/L) decreases the AG by 2.5 mmol/L.

  16. Case AB mixed disturbance • Male, 50 years of age, alcoholic, who has been vomiting had the following laboratory values: • developed a metabolic alkalosis: • If such a patient were then to develop a superimposed alcoholic ketoacidosis

  17. Anion gap Rozděluje metabolické acidózy podle příčiny Zvyšuje se, když jsou v plazmě přítomny ionty jako laktát, anionty ketokyselin nebo sulfáty. Znamená, že acidóza byla způsobena disociací vodíkového iontu z těchto látek AG = Na+ - (HCO3- + Cl-) norma: 11+/- 1 mmol/L

  18. Metabolická acidóza Normální anion gap Ztráty bikarbonátu GIT (průjem) Ledviny – RTA (renal tubular acidosis) Ztráta schopnosti regenerovat bikarbonát Deficit aldosteronu Insensitivita k aldosteronu Renální tubulární acidózy Podání okyselujících chloridových solí Např. Chlorid amonný Zvýšený anion gap zvýšená metabolická produkce kyselin Ketoacidóza Diabetická Alkoholová Hladovění Laktátová acidóza 5-oxoproline* Zvýšený příjem kyselin Toxické látky Salicyláty Etylen glycol methanol Propylene glycol Snížené vylučování kyselin Renální selhání *metabolite formed due to glutathione depletion inacetaminophen/paracetamol intoxicatin

  19. Anion Gap at various causes of metabolic acidosis NH3 Gastrointestinal loss of bicarbonate H+ A- HCO3- Cl- H+ The accumulation of strong acid anions(lactic acidosisketoacidosisuremic acidosis) Cl- NH4+ Cl- Urea Overdosis of NH4Cl K+ Na+ Anion Gap Normal Anion Gap Na+ Na+ Na+ Increased Anion Gap In urine: [K+]+[Na+]-[Cl-] < 0 HCO3- HCO3- HCO3- Cl- Cl- Relative accumulation of chloride NH3 Cl- Cl- HCO3- HCO3- H+ Reduced acidification(tubular acidosis, low-renin hypoaldosteronism) HCO3- Cl- NH4+ K+ Cl- Na+ In urine: [K+]+[Na+]-[Cl-] >= 0

  20. Q3 Které fyziologické parametry ovlivňují velikost glomerulární filtrace (vzorec)? Uveďte příklady chorob a mechanismy, kterými tyto choroby ovlivňují GFR?

  21. Glomerular filtration rate (GFR) • Renal blood flow ~ 20% cardiac output, e.g.~ 1000 mL/min, 1440 L/day • GFR~ 20% of plasma renal flow is filtered, e.i. 2 ml/s, 120 ml/min, ~ 170 L / day !!! • Constant at systemic blood pressure 80 - 180 mmHg (autoregulation)

  22. Factors that influence GFR • GFR = Kf x Filtration pressure • Filtration pressure • Pressure forces that make gradient through the glomerulocapillary membrane • Filtration coefficient (Kf) • Is determined by the properties of the glomerular membrane

  23. Hydrostatic pressure gradient • PG hydrostatic pressure in glomerular capillary (~ 60 - 55 mmHg) • PB hydrostatic pressure in Bowmans (glomerular) capsule (~ 15 mmHg) Primary driving force for glomerular filtration Pressure gradient ~ 43 mmHg

  24. Oncotic pressure gradient • G oncotic pressure in glomerular capillary (~ 25-35 mmHg) • B oncotic pressure in Bowmans (glomerular) capsule (close to 0 mmHg) Partially offsets the hydrostatic pressure gradient and opposes filtration Pressure gradient ~ 30 mmHg

  25. Filtration pressure = (PG – PB) - (G – B) = • Hydrostatic pressure gradient on glomerulo-capillary membrane • Oncotic pressure gradient on glomerulo-capillary membrane ~ (43) - (30)= ~13 mmHg

  26. Filtration coefficient (Kf) • GFR = Kf x Filtration pressure Kf • Is dependent on: • Glomerular capillary surface • Permeability of glomerulo-capillary membrane

  27. Pathologic processes that affect filtration coefficient • Reduction of filtration area • e.g. loss of nephrons (necrosis, nephrectomy) • Decreased permeability of glomerulo-capillary membrane • e.g. glomerulonefritis

  28. Pathologic processes that affect filtration pressure • Decreased capillary hydrostatic preassure (low PG) • e.g. hypotension (bleeding, heart failure, shock) • Increased hydrostatic preassure in Bowmanscapsule(high PB) • urinary tract obstruction • Increased capillary oncotic preassure(highG) • e.g. severe dehydratation (hemoconcentration)

  29. Note • Relationship between glomerular filtration rate and renal artery pressure is not linear across the range of physiologic blood pressures due to autoregulation of filtration pressure and GFR: • autonomous vasoreactive (myogenic) reflex in the afferent arteriole (reflex constriction or dilatation of the afferent arteriole) • tubuloglomerular feedback (sensor: macula densa / effector: adenosin, NO) • angiotensin II–mediated vasoconstriction of the efferent arteriole (sensor: juxtaglomerular cells / effector: local RAAS) • Renal autoregulation usually fails once the systolic blood pressure falls below 80 mmHg • Factors that determine the robustness of the autoregulatory response: • Hyalinosis and myointimal hyperplasia = structural narrowing of the intrarenal arterioles and impaired capacity for renal afferent vasodilation (atherosclerosis, long-standing hypertension, and older age) • In chronic kidney disease, renal afferent vasodilation may be operating at maximal capacity in order to maximize GFR in response to reduced functional renal mass. • Drugs (NSAIDs - inhibit renal prostaglandin production,ACE inhibitors and angiotensin receptor blockers - limit renal efferent vasoconstriction) • Bilateral renal artery stenosis or unilateral renal artery stenosis (in the case of a solitary functioning kidney) • Advanced cirrhosis: Systemic vascular resistance is markedly reduced due to primary arterial vasodilation in the splanchnic circulation, resulting ultimately in activation of vasoconstrictor responses similar to those seen in hypovolemia. • volume depletion and spontaneous bacterial peritonitis

  30. Q4 Jak souvisí pH a kalémie. Proč rychlá korekce dlouhodobé acidémie může být nebezpečná? Vysvětli molekulové mechanismy.

  31. Aproach to alkali therapy • HCO3- can be administered intravenously to raise the serum HCO3- level adequately to increase the pH to greater than 7.20. • Further correction depends on the individual situation and may not be indicated if the underlying process is treatable or the patient is asymptomatic

  32. Metabolic acidosis Alkali therapy is indicated in metabolic acidosis of certain causes Indications for bicarbonate therapy: • chronic renal failure • renal tubular acidosis (RTA) • salicylate intoxication (short-term therapy with bicarbonate to create an alkalemic environment enhances toxin elimination) • warranted in decompensated shock states in patients with a pH of less than 7.15. Not indicated (unless pH drops below 7.1-7.0): • Lactic acidosis (treatment of cause will regenerate bicarbonate – risk of alkalosis) • Ketoacidosis (starvation, diabetes)

  33. Example 1: Alkali therapy of metabolic acidosis is indicated when arterial blood pH < 7.20 and pCO2 at max. compensation (pCO2~15 mmHg – higher for older and ill individuals) • A patient with metabolic acidosis (pH 7.28): • serum HCO3- = 9 mmol/L • a maximally compensated PCO2 = 20 mm Hg • A drop in the serum HCO3- level to 7 mmol/L results in a change in pH from 7.28 to 7.16

  34. Example 2: Alkali therapy of metabolic acidosis is indicated in patients with well-compensated metabolic acidosis with impending respiratory failure • As metabolic acidosis continues in some patients, the increased ventilatory drive to lower the PaCO2 may not be sustainable because of respiratory muscle fatigue. • PaCO2 that starts to rise may change the plasma pH dramatically even without a significant further fall in HCO3-. • A patient with metabolic acidosis with a serum: • pH = 7.33 • HCO3- = 15 mmol/L • compensated PaCO2 = 27 mm Hg • Rise in PaCO2 to 37 mm Hg results in a change in pH from 7.33 to 7.20 • Further rise of the PaCO2 to 43 mm Hg drops the pH to 7.14

  35. Potential complications of bicarbonate therapy • Volume overload • Hypokalemia • CNS acidosis • Hypercapnia • Tissue hypoxia via leftward shift of hemoglobin-oxygen dissociation curve • Alkali stimulation of organic acidosis (lactate) • Overshoot alkalosis

  36. Acidosis and K+ • Metabolic acidosis with acidemia causes a net shift of K+ from the intracellular to the extracellular space. • Conversely, net cellular uptake of K+ is observed in metabolic alkalosis with alkalemia.  • In respiratory acid-base disturbances the effects on K+ redistribution tend to be smaller than metabolic acid-base disturbances.

  37. K+ concentration in the extracellular fluid (ECF) is affected by dietary intake, exchange with the intracellular fluid (ICF), and urinary excretion. Most of the body K+ content resides in the intracellular space of skeletal muscle

  38. Maintenance of extracellular K+ concentration • Is vital particularly for electrical excitability of heart and muscle cells • Maintenance of normal extracellular K+ (3.5 - 5 mmol/L) is under two potential threats: • 98% of the total body content of K+ resides within cells (predominantly skeletal muscle), e.i. small acute shifts of intracellular K+ into or out of the extracellular space can cause severe, even lethal, derangements of extracellular K+concentration.  • Plasma K+ is regulated by the interplay between internal K+ distribution and renal K+ excretion. (K+ loss from the gastrointestinal tract is quite modest under normal conditions)

  39. There is no simple relationship between pH and serum potassium Example (Possible course in patient with diabetic ketoacidosis): Initial hyperkalemia: • Acidemia will tend to shift K+ out of cells and cause hyperkalemia, • Hypertonicity in the absence of insulin will promote K+ release into the extracellular space. Normokalemia: • Renal K+ excretion will be acutely inhibited by acidemia but ultimately enhanced by the increased distal Na+ delivery and flow rate caused by metabolic acidosis and osmotic diuresis in the setting of high aldosterone. Hypokalemia: • Patient may present with marked K+ depletion if osmotic diuresis has been going on for some time. • Renal K+ excretion may later become reduced when GFR falls as volume depletion ensues. • Metabolic acidosis caused by mineral acid (hyperchloremic, nongap acidosis) causes a much larger shift of K+ into the extracellular fluid than does organic acidosis (lactic acidosis).

  40. K+mmol/l B C D H+ H+ H+ H+ H+ H+ K+ K+ K+ K+ K+ K+ K+ K+ D: Quick alkalisation - H+ / K+ exchange dangerous hypokalemia C: Long lasting acidemia - K+ depletion B: Acidemia - K+ / H+ exchange K+ 8 7 H+ H+ 6 K+ Normal kalemia range K+ 5 A 4 3 2 1 A: Norm pH 7,3 7,2 7,0 7,5 7,1 6,9 7,8 7,4 7,6 7,7

  41. Other considerations • Alkalinization by HCO3−administration to be an effective modality for acute treatment of hyperkalemia. • some investigators have failed to find an effect of HCO3−administration to lower plasma K+ in hyperkalemic patients. • An effect of HCO3− administration to lower plasma K+ has been more striking in patients with more severe degrees of pre-existing acidosis than in those with only minimal reductions of plasma HCO3−. • One possible factor modifying the effect of extracellular HCO3− and pH on K+ distribution is the level of intracellular pH and HCO3−. • At any given extracellular pH and HCO3−, Na+entry by Na+-H+ exchange and Na+-bicarbonate cotransport is greater when intracellular pH and HCO3− are reduced, as discussed earlier. • Patients with appreciable pre-existing metabolic acidosis would be expected to have lower intracellular pH and HCO3−. This may account for the fact that the effect of HCO3− administration to reduce plasma K+ has been more striking in patients with pre-existing acidosis. • Effects of pH and HCO3− on internal K+ distribution may be modified by hormonal systems that affect cellular K+ uptake and release. For example, net cellular uptake of K+ is strongly stimulated by insulin because of increased Na+,K+-ATPase activity.There is evidence that stimulation of insulin secretion by acidosis diminishes the hyperkalemia otherwise resulting from acidosis. • Although skeletal muscle is the predominant source of intracellular K+content, there is evidence that the effect of organic acid-induced insulin secretion on plasma K+ is mediated at least in part by hepatic K+ uptake. • The interactions of acid-base disturbances with other hormonal systems are at present incompletely defined.

  42. In lactic acidosis and diabetic ketoacidosis • The organic anion can regenerate bicarbonate when the underlying disorder is corrected • Caution must be exercised in trying to correct the acidosis with bicarbonate therapy, unless the pH is less than 7.0-7.1 • because an overshoot alkalosis may occur

  43. Q5 Pacient, muž 50 let, byl přijat (do VFN v Praze) a má následující hodnoty vyšetření arteriálních krevních plynů při dýchání pokojového vzduchu: PaO2 = 45 mmHg (6 kPa) PaCO2 =30 mmHg (4 kPa) a) Vypočti přibližnou hodnotu pAO2 a P(A-a)O2? Nápověda: Atmosferický tlak při hladině moře je 760 mmHg (101.3 kPa), v nadmořské výšce okolo 240 m.n.m., tj. VFN je přibližně 740 mmHg (98.6 kPa)) Pro uvedený výpočet se počítá s respiračním kvocientem 0.8. b) Jaký P(A-a)O2 gradient byste očekávali u 50-ti letého muže? Odpovídá vypočtený P(A-a)O2 gradient předpokládanému? Při dýchání 60% kyslíku se jeho výsledky vyšetření arteriálních krevních plynů změní následujícím způsobem: PaO2 = 65 mmHg (8.7 kPa) PaCO2= 32 mmHg (4.3 kPa) c) Vypočti přibližnou hodnotu pAO2 a P(A-a)O2 po aplikaci 60% kyslíku u pacienta? d) Jaká je příčina minimální změny PaO2 u pacienta a jaká je diferenciální diagnóza u tohoto stavu?

  44. Equation for derivation of alveolar PO2 (PAO2) PAO2 = Inspired oxygen (PiO2) – consumed oxygen • The calculation relies on the following assumptions: • Inspired gas contains no carbon dioxide (CO2) = for calculation PiCO2 = 0 mmHg [in real PiCO2 = 0.3 mmHg] • Other gases (e.g. nitrogen) except oxygen in the inspired air are in equilibrium with their dissolved states in the blood • The alveolar and arterial partial pressures of CO2 are equal pACO2 = PaCO2 [in real 1-2 mmHg difference] • The alveolar gas is fully saturated with water vapors • Daltons law applies • Total pressure of gases in a mixture is equal to the sum of the partial pressures of the constituent gases (for air: PO2 + PCO2 + PN2 + PH2O+ Pother gases = PB (barometric pressure)

  45. Equation for derivation of alveolar PO2 (PAO2)

  46. Abbreviations • PiO2 = Partial pressure of inspired oxygen (dependent on PB and FiO2) • FiO2 = Fraction of inspired oxygen (0.21) • PB = Barometric pressure (at sea level 760 mmHg or 101.3 kPa) • PH2O = Partial pressure of water vapor at 37°C • RQ* = Respiration coefficient VCO2 / VO2 = ratio of carbon dioxide production to oxygen consumption (0.8) • PAO2 = Partial Alveolar pressure of O2 • PaO2 = Partial arterial pressure of O2 • PACO2 = Partial arterial pressure of CO2 • * If patient is on i.v. glucose RQ would be close to 1, if patient is hypoglycemic or diabetic (fatty acid metabolism) RQ is rather 0.7.

  47. Calculation case IS for VFN patient: • PAO2 = PiO2 - (PaCO2 / RQ) = inspired oxygen – consumed oxygen At VFN (PB: ~ 740 mmHg) • PiO2 = (PB – PH2O) * FiO2 = (740-47) * 0.21 = 146 mmHg • PAO2 = 146 –(30/0.8) = 110 mm Hg • P(A-a)O2 = 110 - 45 = 65 mmHg (elevated) At sea level (PB: ~ 760 mmHg) • PAO2 = 150 – 1.2(30) = 114 mm Hg • P(A-a)O2 = 114 - 45 = 69 mmHg (elevated)

  48. Calculation case IS for VFN patient (oxygen therapy): • PiO2 = (PB – PH2O) * FiO2 = (740-47) * 0.6 = 415.8 mmHg • PAO2 = 416 – (32/0.8) = 376 mmHg • P(A-a)O2 = 376 - 65 = 311 mmHg elevated

  49. Interpretation of P(A-a)O2 gradient Several approaches: Normal P(A-a)O2 • P(A-a)O2 <12 mm Hg Expected P(A-a)O2 is corrected for age • P(A-a)O2 < Age/4 + 4 (in mmHg) • P(A-a)O2 < 8 + (20% of the patient's age) (in mmHg)

  50. Result • PAO2 = 110 mmHg • PaO2 = 45 mmHg • P(A-a)O2 = 65 mmHgelevated Oxygen therapy: • minimal elevation in PaO2 • shunt major cause of hypoxemia

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