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What is the main buffering system in the body and why?

Bicarbonate, as it can "convert" protons to carbon dioxide, an easily eliminated gaseous acid through the lungs.
*without a buffering system, normal body acid production would make us drop 5 pH units


Were bicarbonate not to be re-synthesized as it is lost due to "suicide" by converting H+ to CO2, how long would it last?

5-6 days before the 24mM*15L = 360mmol supply was destroyed


Besides reabsorbtion of bicarb from the glomerular filtrate, how does the kidney compensate for bicarb lost by CO2 elimination?

• It produces bicarbonate in the tubule


In the obligatory reabsorption phase of bicarb in the proximal tubule, what is going on?

• Bicarb is filtered through the glomerulus because it is water soluble
• The Na/H+ exhanger on the apical surface of the proximal tubular epithelium will exchange sodium for protons, meaning more H+ are in the lumen
• The H+ and bicarb will make carbonic acid which will meet lumenal CA (how does that get there????)
• CA will make H20 and CO2, and the CO2 will then freely diffuse across the apical membrane
• In the cell, CO2 makes Carbonic acid again (reversible equation) and bicarb is synported with Na out of the cell through the basolateral side


What are the cellular transporters in the intercalated cells responsible for synthesizing bicarb?

• Apical H+ pump (ATPase) that churns out H+ to the lumen
• Intracellular carbonic anhydrase enzyme that separates carbonic acid to H+ and HCO3-
• The BCE or Bicarb/Cl exchanger on the basolateral side that brings in Cl while pumping HCO3- into the ECF
• The cl coming in will balance the electricity of the movement


The constant pumping of H+ into the lumen is not an insurmountable electrochemical gradient problem why?

• Acid is trapped in the lumen by urinary buffers, usually different forms of other acidic anions (????)
• Like HPO4 + H+ --> H2PO4
*creatinine and urate are other "titrateable buffers"


How does the process of ammonia trapping work?

• Ammonia is readily soluble and neutral so it diffuses through the apical membranes of tubule epithelium
• Binds H+ IN THE LUMEN and forms NH4 or ammonium, which is charged and can't get back across the apical membrane


How much bicarb need be made each day to account for losses?

• 60-70mmol
*compared to the 4320mmol of bicarb that have to be reabsorbed from the filtrate, that is a pretty small number


When it comes to thinking about Bicarb synthesis and reabsorption, what's the good rule of thumb?

There can be no bicarb synthesis untill bicarb reabsorption is complete. Pretty much the same machinery is used for both so reabsorption takes priority
* this is why only the very distal cells (intercalated cells) can actually net PRODUCE bicarb


What are the rate limiting processes for bicarbonate homeostasis?

• Apical secretion of hydrogen ions and basolateral extrusion of bicarbonate
• The cellular machinery that pumps out and in
• Also need to remember that the rates of these processes depend on ECF pH and CO2 levels


Why does the rate of apical hydrogen ion secretion and basolateral bicarb extrusion depend on ECF pH and CO2?

• Not really known WHY but there is an increase in the number of pumps in cases of acidosis


How does acid/base status affect potassium?

• Alkalosis leads to increased potassium excretion and HYPOkalemia
• Remember, increase pH, decrease K, decrease pH, increase K


Why does hypokalemia CAUSE alkalosis?

• Already know that alkalosis cuases hypokalemia…
• Lower ECF potassium will drive H+ into the cell
• Incrased H+ in the cell PLUS the increased H+ pumps due to chronic pH drop (intracellular) will mean inappropriate levels of H+ transport into the lumen
• End result is loss of H+ in the urine so that an alkalotic state is reached


What happens to the pH in hyperkalemia?

• Kinda the opposite of hypokalemia, namely an acidotic state, but for slightly different reasons
• Same reasons = number of apical H+ pumps fall and their rate of pump falls due to lower concentrations of H+ in the cell, resulting in more H+ in ECF
• Different reasons = potassium INdirectly (somehow) interferes with H+ secretion into urine through DIRECTLY messing with ammonia trapping


What is the normal serum pH and what does that correspond to in terms of H+ concentration?

• 7.35 - 7.45, 35 - 45nM


What is the simplified Henderson Hasselbach equation that shows what mainly determines serum pH?

• pH = pK + log[HCO3]/[PCO2]
• Essentially, acidity = bicarbonate/carbon dioxide


How many types of acid base disturbances can there be in the body?

• Only four because acidity is determined by the ratio of bicarbonate to carbon dioxide
• Respiratory alkalosis (decrease in CO2 resulting in an increase in pH)
• Respiratory acidosis (increase in CO2 resulting in a decrease in pH)
• Metabolic alkalosis (increase in HCO3 resulting in an increase in pH)
• Metabolic acidosis (decrease in HCO3 resulting in a decrease in pH)


In what "direction" is the compensation for an acid-base disturbance?

• ALWAYS in the same direction as the original imbalance
• Thus, in the case of lowered PCO2, compensation is a lowered bicarb
• If raised PCO2, increased bicarb
• Acidity = bicarb/PCO2


What are the "textbook" numbers that are used for acid base disturbances?

• pH = 7.4
• PCO2(mmHg) = 40
• HCO3(mEq/L)= 24


What is the definition of respiratory alkalosis?

• Respiratory process that causes a primary decrease in the PCO2 and thus raises the blood pH


What is the compensation for primary respiratory alkalosis?

• Decreased HCO3 from the cells releasing H+ and renal H+ retention
• The cells releasing H+ is acute
• Renal retention of H+ is chronic (3-5 days to complete)
• H+ binding to HCO3 will destroy it into water and CO2, thus lowering overall bicarb
• RULE (acute) - bicarb drobs 2mEq/L for every 10mmHg fall in PCO2
• RULE (chronic) - bicarb falls by 4mEq/L for every 10mmHg fall in PCO2


What's the ddx with respiratory alkalosis?

• Primary is ALWAYS from breathing too much/hyperventilating
• Hyperventilation ddx
• Non-central= pulmonary diseases, hypoxemia, voluntary, mechanical ventilation,
• Central = fever, liver disease, pregnancy, head injuries, salicylate toxicity (causing a concurrent metabolic acidosis)


What is the compensation rule for acute respiratory alkalosis?

• RULE (acute) - bicarb drobs 2mEq/L for every 10mmHg fall in PCO2
• RULE (chronic) - bicarb falls by 4mEq/L for every 10mmHg fall in PCO2


What is the compensation rule for chronic respiratory alkalosis?

• RULE (acute) - bicarb drobs 2mEq/L for every 10mmHg fall in PCO2
• RULE (chronic) - bicarb falls by 4mEq/L for every 10mmHg fall in PCO2


What lab abnormalities, symptoms and consequences of respiratory alkalosis would you expect to see?

• Lab - decreased potassium (small), decreased phosphorus (large)
• Symptoms - neurologic (parasthesias and carpopedal spasms)
• Consequences - decreased ICP, cardiac arrhythmias


What's the treatment for respiratory alkalosis?

Treat underlying cause of hyperventilation. If over 7.5, give a sedative to lower breathing rate to prevent major complications like cardiac arrhythmias and tetany


What is the definition of respiratory acidosis?

• Respiratory process that causes a primary increase in PCO2 and thus lowers the serum pH


What's the differential ddx for respiratory acidosis?

○ Sensing and signalling (processes that impair the medullary control center like sedatives, OHS, Guillian-barre, amyotrophic lateral sclerosis)
○ Muscles and motion (impair function of the respiratory muscles like hypokalemia, periodic paralysis)
○ Free flow (impair the free flow of air resulting in airway obstruction like a foreign body)
○ Gas exchange (processes that impair the exchange of CO2 and O2 in the alveoli like pneumonia, acute lung injury, COPD)


What is the compensation for respiratory acidosis?

1) cell buffering (acute)

2) Renal H+ excretion/HCO3 resorption = chronic

*renal compensation occurs by the renal excretion of H+ which results in the generation of new bicarb, takes 3-5 days to reach completion
*RULE - increase bicarb 1mEq/L for every 10Torr PCO2 increase (acute) and 4mEq/L change for 10Torr change (chronic)


How can you predict the expected increase in bicarb during respiratory acidosis?

Acute = change in bicarb should increase 1mEq/L for every 10mmHg increase in PCO2

Chronic (3-5 days) - change in bicarb should be 4mEq increase for every 10mmHg increase in PCO2


What presenting symptoms make you suspect respiratory acidosis?

headache, decreased arousal or increased somnolence (CO2 narcosis).
*this eventually results in increased ICP, cardiac arrhythmias, hypotension from peripheral vasodilation
*Hypercapnia = Stimulation of ventilation via both central and peripheral chemoreceptors
Cerebral vasodilation increasing cerebral blood flow and intracranial pressure
Stimulation of the sympathetic nervous system resulting in tachycardia, peripheral vasoconstriction and sweating
Peripheral vasodilation by direct effect on vessels
Central depression at very high levels of pCO2


What is the definition of metabolic alkalosis?

metabolic process that causes a primary increase in HCO3
*2 step process = generation and maintanence
Generation= addition of bicarb, loss of H+, loss of chloride ("contraction alkalosis"), post-hypercapnia, hypokalemia
Maintenance = kidney's fault due to inability to excrete excess bicarb, often due to chloride depletion or potassium depletion (affects the ion transport)


What medical treatments can cause an overall addition of bicarb?

direct admin of bicarb (medical treatment of metabolic acidosis)
direct admin of a substrate that is metabolized to bicarb (lactated ringers or lactate)


How can you lose H+ and become alkalotic?

GI loss from vomiting or NG suctioning
Renal loss through loop and thiazide diuretics and mineralocorticoid excess


When might a patient have metabolic alkalosis because of a hypercapneic treatment?

with chronic respiratory acidosis (COPD) bicarb is increased to compensate. after treatment with oxygen there is a transitory period where the bicarb will not be balanced for the level of acidosis
*after mechanical ventilation and development of metabolic alkalosis, it is maintained by chloride depletion which prevents excretion of the excess bicarb


Describe the kidney's maintenance of a metabolic alkalosis

kidney normally respons to elevated serum bicarb by increasing excretion of bicarb, so problems with bicarb in the kidneys is ALWAYS an excretion problem
*chloride depletion
*K depletion
*increased mineralocorticoid activity


How does chloride depletion lead to the maintenance of a metabolic alkalosis?

*chloride depletion results in the resorption of bicarb by the kidney
*20mEq/L urine chloride refers to chloride responsive vs. un-responsive alkalosis (under is responsive, over is un-responsive)
*potassium depletion messes with aldosterone release and also affects bicarb excretion in another unknown way
*increased aldosterone or mineralocorticoid secretion acts on the H+ ATPase pump in the intercalated cell in the distal tubule and that leads to H+ excretion and bicarb resorption


How does hyperaldosteronism or cushings syndrome lead to metabolic alkalosis?

*increased aldosterone or mineralocorticoid secretion acts on the H+ ATPase pump in the intercalated cell in the distal tubule and that leads to H+ excretion and bicarb resorption
*water dissociates to H+ and OH-, and the H+ is secreted by the pump, leaving OH- to combine with CO2 to make more bicarb which is transported to the interstitium and thus resorbed


How is the clinical diagnosis of metabolic alkalosis divided?

Into 2 categories: chloride responsive and chloride un-responsive
*also known as saline responsive and resistent, respectively)
*this is measured by urine chloride


what is going on in a urine sample with chloride under 20mEq/L?

chloride responsive metabolic alkalosis
*low urine chloride reflects chloride depletion as the major maintenance factor
*typically associated with a loss of intravascular volume responsive to normal saline admin
*gives you a specific differential = diuretics, vomiting, villous adenomas, congenital chloride losing diarrhea, CF, post hypercapnia


What is the differential for chloride resistant metabolic alkalosis?

urine chloride OVER 20mEq/L
*excess mineralocorticoids from hyperaldosteronism or cushing's syndrome
*licorice ingestion
*both of these things leading to H+ pump action and losing H+ in urine, increasing bicarb resorption


What is the compensation expected for metabolic alkalosis?

Increased PCO2 from hypoventilation
*expect CO2 change = 0.25 to 1 * change in bicarb
*this reflects a range, outside of which there is something else going on


What is the treatment for metabolic alkalosis?

Prevent cardiac arrhythmias and hypocalcemia
*alkalemia increases sensitivity to catecholamines and may precipitate life-threatening arrhythmias
*alkalosis increases binding of free calcium to albumin so there is lower ionized (free) calcium in the blood. this increases neuromuscular irritability
*can treat with mechanical ventilation and forced hypoventilation
*NaCl infusions in chloride responsive alkalosis
*block mineralocorticoid action in chloride resistant alkalosis with spironolactone or amiloride


What is the definition of metabolic acidosis?

metabolic process that causes a primary decrease in bicarb
*occurs by loss of bicarb or addition of an acid
*look at serum anion gap. Normal is 10
*elevated = acidosis by way of some organic acid being added


How do you determine the serum anion gap?

Sodium - chloride - bicarb
*normal is 9+/-3 (6-12)
*over 18 is the rule of thumb for anion gap metabolic acidosis


What's going on in non-anion gap metabolic acidosis?

Loss of bicarb is shifting cells to make more by making H+, which lowers the blood pH
*the loss of bicarb is replaced by a gain in chloride to fill in the "anion gap" and keep it a non-anion gap metabolic acidosis


What is meant by "corrected" anion gap?

Albumin (serum protein) is a major contributor to the anion gap
*change in serum albumin of 1g/dL changes anion gap by 2.5.
*so look at albumin levels (like in nephrotic syndrome) to see if there should be a true anion gap acidosis or not in the context of tubular injury or glomerular injury


Bicarb loss causing acidosis can be from the kidney in what condition?

RTA = renal tubular acidosis
*defect in renal bicarb or H+ handling
*three major forms are proximal, distal, hyperkalemic


What is the normal renal process for handling bicarb and H+?

Two steps
1)bicarb reabsorption in the proximal tubule
2)H+ excretion in the distal tubule that generates new bicarb
*if the proximal tubule is damaged and doesn't resorb the normal 90% of filtered HCO3 then there is PROXIMAL RTA
*check urine pH to see if there is a kidney problem that will result in the acidemia


What can you check in the urine to see if renal acid excretion and new bicarb generation is appropriate?

You can check the urine pH and urine anion gap
*urine pH = normally should decrease if there is a metabolic acidosis present. If pH is >5.3 in non-anion gap metabolic acidosis then there is likely RTA present. If pH


what is the pH of the urine that makes you think RTA?

if pH is >5.3 in the setting of non-anion gap metabolic acidosis you are losing bicarb from the kidneys due to Renal Tubular Acidosis
*the other option is GI loss and that is reflected by acidic urine (pH


Positive urine anion gap means what?

likely a RTA or renal tubular acidosis problem. A kidney-specific loss of bicarb that is the source of the metabolic acidosis.
(urine numbers) sodium + potassium - chloride


Addition of an acid that can lead to anion gap metabolic acidosis can be caused by what?

1) ingestion of some toxin that interfere with metabolism (aspirin) or is itself metabolized (MUDPILES) into an acid
2) overproduction of organic acid because of underlying metabolic issue (DM thus ketoacidosis, or lactic acidosis)
3) failure to excrete H+ and anions normally made by the body because of renal failure


What is the pneumonic KARL helpful for?

remembering the 4 most common causes of anion gap metabolic acidosis
*full ddx is MUDPILES
K= ketoacidosis (diabetic, alcoholic, starvation)
A= aspirin and other toxins (salicylate, methanol, ethylene glycol)
R= renal failure
L= lactic acidosis (ischemia, mitochondrial derangement, gut bacteria producing D-stereoisomer)


If the history suggests anion gap metabolic acidosis, and you don't see it, what serum lab value should you pay attention to?

Albumin. Serum albumin is a contributer to the anion gap.
*corrected anion gap is every 1g/dL change in albumin is a 2.5mEq/L change in the anion gap (opposite directions).
*example = loss of 1g/dL (from 4 to 3) will mean an anion gap on the border of normal at 16 is now 18.5 and definately indicative of an anion gap


What are the physiological effects of metabolic acidosis?

*when really bad (7.00-7.1), myocardial contractility is depressed and peripheral resistance falls = hypotension, pulmonary edema and vfib
*likely due to depressing vascular and myocardial responsiveness to catecholamines
*Kussmaul breathing or hyperventilating to blow off CO2
*chronic metabolic acidosis causes hypercalciuria and bone disease
*thus must treat loss of calcium in RTA or acidosis of chronic renal failure


What is the expected compensation for metabolic acidosis?

increasing ventilation and causing a fall in PCO2. the primary cause is a drop in bicarb that in turn drops the serum pH
*peripheral carotid chemoreceptors and CNS receptors increase ventilation and thereby CO2 excretion
* expected CHANGE in PaCO2 = 1 - 1.5 * change in bicarb (given as a range, outside of which means the process in question is not a "simple" metabolic acidosis)
*remember to do this you have to know regular PCO2 in Denver is 35 and at sea level is 40 and normal bicarb is 24


What's a quick way of seeing simple metabolic acidosis by just looking at PCO2 and pH?

the last 2 digits of pH should = last 2 digits of PCO2
*example = normal pH is 7.4. Acidosis of 7.25 means PCO2 should be 25 (instead of 40)
*if you don't see this happening then there is likely a mixed disorder going on


What if the change in PaCO2 is greater than 1-1.5*change in bicarb?

That is indicative of a mixed process, and in particular a primary respiratory alkalosis coexisting with a metabolic acidosis


What is the treatment strategy for metabolic acidosis?

correct the underlying problem that is adding acid to the body.
*chronic acidosis, can use oral sodium bicarb to correct bicarb levels
*in ACUTE acidosis, giving bicarb is generally a bad idea and may cause problems in the heart


What is a mixed acid base disturbance?

coexistence of two or more primary acid-base disorders. The compensation rules don't pan out and the compensation is less or more than you might expect (pH does not return to normal).
*if the PCO2 and bicarb differ from normal in opposite directions, mixed disorder is always present


What is the 6-step approach to acid-base problems?

1) Acidemic or alkalemic?
2) respiratory or metabolic?
3) acute or chronic?
4) increased anion gap? If serum is normal, urine anion gap?
5) if metabolic, is there appropriate respiratory compensation?
6) if metabolic, are there other hidden acid-base disturbances present?


What is the delta-delta rule?

*step 6 of the 6-step acid-base pathway
*compares change in bicarb with the change in serum anion gap.
*if one disorder is present, the change in bicarb should equal the change in the serum anion gap
*if there is more bicarb than expected, there is a hidden metabolic alkalosis
*if there is less bicarb than expected, there is a hidden metabolic acidosis