Episode 44: Welcome to this bi-weekly series of Goljan-inspired USMLE review MP3’s. I’ll go through my personal notes that I used to prepare for Step 1 first, then Step 2 Clinical Knowledge. My style is more direct, no stories or shame on you if you’re not studying enough. Get access to all of the MP3’s and high yield notes by joining Medical-Mastermind-Community.com and study on-the-go!
Listen to the sample here…
I. Hypoxia = inadequate oxygenation of tissue (same definition of as shock). Need O2 for
oxidation phosphorylation pathway – where you get ATP from inner Mito membrane (electron transport system, called oxidative phosphorylation). The last rxn is O2 to receive the electrons. Protons are being kicked off, go back into the membrane, and form ATP, and ATP in formed in the mitochondria.
1. Oxygen content = Hb x O2 satn + partial pressure of arterial oxygen (these are the 3 main things that carry O2 in our blood) In Hb, the O2 attaches to heme group (O2 sat’n)
Partial pressure of arterial O2 is O2 dissolved in plasma. In RBC, four heme groups (Fe must be +2; if Fe+ is +3, it cannot carry O2). Therefore, when all four heme groups have an O2 on it, the O2 sat’n is 100%.
2. O2 sat’n is the O2 IN the RBC is attached TO the heme group = (measured by a pulse oximeter)
3. Partial pressure of O2 is O2 dissolved in PLASMA O2 flow: from alveoli through the interphase, then dissolves in plasma, and increases the partial pressure of O2, diffuses through the RBC membrane and attaches to the heme groups on the RBC on the Hb, which is the O2 sat’n. Therefore – if partial pressure of O2 is decreased, O2 sat’n HAS to be decreased (B/c O2 came from amount that was dissolved in plasma)
B. Causes of tissue hypoxia:
1. Ischemia (decrease in ARTERIAL blood flow ……NOT venous). MCC Ischemia is thrombus in muscular artery (b/c this is the mcc death in USA = MI, therefore MI is good example of ischemia b/c thrombus is blocking arterial blood flow, producing tissue hypoxia).
Other causes of tissue ischemia: decrease in Cardiac Output (leads to hypovolemia and cardiogenic shock) b/c there is a decrease in arterial blood flow.
2. 2nd MCC of tissue hypoxia = hypoxemia
Hypoxia = ‘big’ term
Hypoxemia = cause of hypoxia (they are not the same); deals with the partial pressure of O2 in the tissues.
3. Arterial O2 (O2 dissolved in arterial plasma, therefore, when the particle pressure of O2 is decreased, this is called hypoxemia).
C. Here are 4 causes of hypoxemia:
1. Resp acidosis (in terms of hypoxemia) – in terms of Dalton’s law, the sum of the partial pressure of gas must = 760 at atmospheric pressure (have O2, CO2, and nitrogen; nitrogen remains constant – therefore, when you retain CO2, this is resp acidosis; when CO2 goes up, pO2 HAS to go down b/c must have to equal 760. Therefore, every time you have resp acidosis, from ANY cause, you have hypoxemia b/c low arterial pO2; increase CO2= decrease pO2, and vice versa in resp alkalosis).
2. Ventilation defects – best example is resp distress syndrome (aka hyaline membrane dz in children). In adults, this is called Adult RDS, and has a ventilation defect. Lost ventilation to the alveoli, but still have perfusion; therefore have created an intrapulmonary shunt. Exam question: pt with hypoxemia, given 100% of O2 for 20 minutes, and pO2 did not increase, therefore indicates a SHUNT, massive ventilation defect.
3. Perfusion defects – knock off blood flow
MCC perfusion defect = pulmonary embolus, especially in prolonged flights, with sitting down and not getting up. Stasis in veins of the deep veins, leads to propagation of a clot and 3-5 days later an embolus develops and embolizes. In this case, you have ventilation, but no perfusion; therefore there is an increase in dead space. If you give 100% O2 for a perfusion defect, pO2 will go UP (way to distinguish vent from perfusion defect), b/c not every single vessel in the lung is not perfused.
Therefore, perfusion defects because an increase in dead space, while ventilation defects cause intrapulmonary shunts. To tell the difference, give 100% O2 and see whether the pO2 stays the same, ie does not go up (shunt) or increases (increase in dead space).
4. Diffusion defect – something in the interphase that O2 cannot get through…ie fibrosis. Best example–Sarcoidosis (a restrictive lung disease); O2 already have trouble getting through the membrane; with fibrosis it is worse. Another example–Pulmonary edema; O2 cannot cross; therefore there is a diffusion defect. Another example is plain old fluid from heart failure leads to dyspnea, b/c activated the J reflex is initiated (innervated by CN10); activation of CN10, leads to dyspnea (can’t take a full breath) b/c fluid in interstium of the lung, and the J receptor is irritated.
These are the four things that cause hypoxemia (resp acidosis, ventilation defects, perfusion defects, and diffusion defects).
3. Hemoglobin related hypoxia
In the case of anemia, the classic misconception is a hypoxemia (decrease in pO2). There is NO hypoxemia in anemia, there is normal gas exchange (normal respiration),
therefore normal pO2 and O2 saturation, but there is a decrease in Hb. That is what anemia is: decrease in Hb. If you have 5 gm of Hb, there is not a whole lot of O2 that
gets to tissue, therefore get tissue hypoxia and the patient has exertional dyspnea with anemia, exercise intolerance.
a. Carbon monoxide (CO): classic – heater in winter; in a closed space with a heater (heater have many combustable materials; automobile exhaust and house fire. In the
house fire scenario, two things cause tissue hypoxia: 1) CO poisoning and 2) Cyanide poisoning b/c upholstery is made of polyurethrane products. When theres heat, cyanide
gas is given off; therefore pts from house fires commonly have CO and cyanide poisoning.
CO is very diffusible and has a high affinity for Hb, therefore the O2 SAT’N will be decreased b/c its sitting on the heme group, instead of O2 (remember that CO has a 200 X affinity for Hb). (Hb is normal – its NOT anemia, pO2 (O2 dissolved in plasma) is normal, too); when O2 diffuses into the RBC, CO already sitting there, and CO has a higher affinity for heme.
To treat, give 100% O2. Decrease of O2 sat’n = clinical evidence is cyanosis Not seen in CO poisoning b/c cherry red pigment MASKS it, therefore makes the diagnosis hard to make. MC symptom of CO poisoning = headache.
Methemoglobin is Fe3+ on heme group, therefore O2 CANNOT bind. Therefore, in methemoglobin poisoning, the only thing screwed up is O2 saturation (b/c the iron is +3, instead of +2). Example: pt that has drawn blood, which is chocolate colored b/c there is no O2 on heme groups (normal pO2, Hb concentration is normal, but the O2 saturation is not normal); “seat is empty, but cannot sit in it, b/c it’s +3”. RBC’s have a methemoglobin reductase system in glycolytic cycle (reduction can reduce +3 to +2).
Example: Pt from rocky mountains was cyanotic; they gave him 100% O2, and he was still cyanotic (was drinking water in mtns – water has nitrites and nitrates, which are oxidizing agents that oxidize Hb so the iron become +3 instead of +2). Clue was that O2 did not correct the cyanosis. Rx: IV methaline blue (DOC); ancillary Rx = vitamin C (a reducing agent). Most recent drug, Dapsone (used to Rx leprosy) is a sulfa and nitryl drug. Therefore does two things: 1) produce methemoglobin and 2) have potential in producing hemolytic anemia in glucose 6 phosphate dehydrogenase deficiencies.
Therefore, hemolysis in G6PD def is referring to oxidizing agents, causing an increase in peroxide, which destroys the RBC; the same drugs that produce hemolysis in G6PD def. are sulfa and nitryl drugs. These drugs also produce methemoglobin.
Therefore, exposure to dapsone, primaquine, and TMP-SMX, or nitryl drugs (nitroglycerin/nitroprusside), there can be a combo of hemolytic anemia, G6PD def, and methemoglobinemia b/c they are oxidizing agents. Common to see methemoglobinemia in HIV b/c pt is on TMP-SMX for Rx of PCP. Therefore, potential complication of that therapy is methemoglobinemia.
c. Curves: left and right shifts
Want a right shifted curve – want Hb with a decreased affinity for O2, so it can release O2 to tissues. Causes: 2,3 bisphosphoglycerate (BPG), fever, low pH (acidosis), high altitude (have a resp alkalosis, therefore have to hyperventilate b/c you will decrease the CO2, leading to an increase in pO2, leading to a right shift b/c there is an increase in synthesis of 2,3 BPG).
Left shift – CO, methemoglobin, HbF (fetal Hb), decrease in 2,3-BPG, alkalosis. Therefore, with CO, there is a decrease in O2 sat’n (hypoxia) and left shift.
4. Problems related to problems related to oxidative pathway
a. Most imp: cytochrome oxidase (last enzyme before it transfers the electrons to O2. Remember the 3 C’s – cytochrome oxidase, cyanide, CO all inhibit cytochrome oxidase.
Therefore 3 things for CO – (1) decrease in O2 sat (hypoxia), (2) left shifts (so, what little you carry, you can’t release), and (3) if you were able to release it, it blocks cytochrome oxidase, so the entire system shuts down.
b. Uncoupling – ability for inner mito membrane to synthesize ATP. Inner mito membrane is permeable to protons. You only want protons to go through a certain pore, where ATP synthase is the base, leading to production of ATP; you don’t want random influx of protons – and that is what uncoupling agents do. Examples: dinitrylphenol (chemical for preserving wood), alcohol, salicylates. Uncoupling agents causes protons to go right through the membrane; therefore you are draining all the protons, and very little ATP being made. B/c our body is in total equilibrium with each other, rxns that produce protons increase (rxns that make NADH and FADH, these were the protons that were delivered to the electron transport system).
Therefore any rxn that makes NADH and FADH that leads to proton production will rev up rxns making NADH and FADH to make more protons. With increased rate of rxns, leads to an increase in temperature; therefore, will also see HYPERTHERMIA. Complication of salicylate toxic = hyperthermia (b/c it is an uncoupling agent). Another example: alcoholic on hot day will lead to heat stroke b/c already have uncoupling of oxidative phosphorylation (b/c mito are already messed up).
These are all the causes of tissue hypoxia (ischemia, Hb related, cyto oxidase block, uncoupling agents). Absolute key things!
5. What happens when there is:
a. resp acidosis – Hb stays same, O2 sat’n decreased, partial pressure of O2 decreased (O2 sat decreased b/c pO2 is decreased)
b. anemia – only Hb is affected (normal O2 sat’n and pO2)
c. CO/methemoglobin – Hb normal, O2 sat’n decreased, pO2 normal Rx CO – 100% O2; methemo – IV methaline blue (DOC) or vit C (ascorbic acid)
d. Decreased of ATP (as a result of tissue hypoxia)
1. Most imp: have to go into anaerobic glycolysis; end product is lactic acid (pyruvate is converted to lactate b/c of increased NADH); need to make NAD, so that the NAD can feedback into the glycolytic cycle to make 2 more ATP. Why do we have to use anaerobic glycolysis with tissue hypoxia? Mitochondria are the one that makes ATP; however, with anaerobic glycolysis, you make 2 ATP without going into the mitochondria.
Every cell (including RBC’s) in the body is capable of performing anaerobic glycolysis, therefore surviving on 2 ATP per glucose if you have tissue hypoxia. Mitochondrial system is totally shut down (no O2 at the end of the electron transport system – can only get 2 ATP with anaerobic glycolysis).
Good news – get 2 ATP
Bad news – build up of lactic acid in the cell and outside the cell (increased anion-gap metabolic acidosis with tissue hypoxia) due to lactic acidosis from anaerobic glycolysis. However, causes havoc inside the cell b/c increase of acid within a cell will denature proteins (with structural proteins messed up, the configuration will be altered); enzymes will be denatured, too. As a result, cells cannot autodigest anymore b/c enzymes are destroyed b/c
buildup of acid. Tissue hypoxia will therefore lead to COAGULATION necrosis (aka infarction). Therefore, buildup of lactic acid within the cell will lead to Coagulation necrosis.
2. 2nd problem of lacking ATP: all ATP pumps are screwed up b/c they run on ATP. ATP is the power, used by muscles, the pump, anything that needs energy needs ATP.
Na/K pump – blocked by digitalis to allow Na to go into cardiac muscle, so Ca channels open to increase force of contraction (therefore, sometimes you want the pump blocked), and sometimes you want to enhance it.
With no ATP, Na into the cell and it brings H20, which leads to cellular swelling (which is reversible). Therefore, with tissue hypoxia there will be swelling of the cell due to decreased ATP (therefore will get O2 back, and will pump it out – therefore it is REVERSABLE). In true RBC, anaerobic glycolysis is the main energy source b/c they do not have mitochondria; not normal in other tissues (want to utilize FA’s, TCA, etc).
3. Cell without O2 leads to irreversible changes.
Ca changes with irreversible damage – Ca/ATPase pump. With decrease in ATP, Ca has easy access into the cell. Within the cell, it activates many enzymes (ie phospholipases in the cell membranes, enzymes in the nucleus, leading to nuclear pyknosis (so the chromatin disappears), into goes into the mito and destroys it). Ca activates enzymes; hypercalcemia leads to acute pancreatitis b/c enzymes in the pancreas have been activated.
Therefore, with irreversible changes, Ca has a major role. Of the two that get damaged (mito and cell membrane), cell membrane is damaged a lot worse, resulting in bad things from the outside to get into the cell. However, to add insult to injury, knock off mitochondria (energy producing factory), it is a very bad situation (cell dies)…CK-MB for detecting a myocardial infarction.
How to calculate the anion gap to detect the presence of extra anions (poisons) in the blood.
Anion Gap = Na + K – Cl – HCO3 (normal is 8-12)
Differential diagnosis for an anion gap acidosis.
Note: a useful mnemonic to remember this is MUDPILES (methanol, uremia, DKA, propylene glycol, INH, lactic acidosis, ethylene glycol, salicylates). Historically, the “P” in MUDPILES was for paraldehyde. Paraldehyde is no longer used medically, so the “P” in the MUDPILES mnemonic currently refers to Propylene glycol, a substance common in pharmaceutical injections such as diazepam or lorazepam. Accumulation of propylene glycol is converted into lactate and pyruvate which causes lactic acidosis.