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ACID-BASECLINICAL PHYSIOLOGY
Jayson Rapoport
Faculty of Medicine,
Hebrew University, Jerusalem
Department of Nephrology,
Kaplan Medical Center, Rehovot
Acid-Base: Physiology (1)
[H+] maintained within relatively narrow
limits: Normal [H+] = 40nM/L
(40 x 10-9M/l)
(compare to [Na+]: 140mM/l, or
140 x 10-3M/l.)
Usually expressed as pH
pH = -log [H+]
= -log [40 x 10-9] = 7.4
Acid-Base: Physiology (2)
Maintenance of constant pH is
important because H+ is very reactive,
especially with proteins, and
reaction changes protein function –
Probably most important are proteins
in brain
Acid-Base: Physiology (3)
Definitions:
ACID: substance that donates H+
BASE: substance that accepts H+
ACID
H2CO3
HCl
NH4+
BASE
H+ + HCO3H+ + ClH+ + NH3
Acid-Base: Physiology (4)
2 types of acid produced in body:
1. CARBONIC: produced by metabolism of CO2
and fats: 15,000mM of CO2. This acid is
excreted via lungs.
2. NON-CARBONIC (FIXED) ACIDS: produced
by metabolism of proteins: 50-100mM
produced/day (or about 1mM/kg body weight).
These H+ must be excreted in urine.
Stages of acid-base balance
1.
Acid synthesis:
-S-containing AA, phosphoesters (H3PO4), organic
acids from foods (Total production 1-1.5meg/kg/day)
2. Buffering:
-HCO3-H2CO3
-Albumin
-Hemoglobin
3. Renal Acid Secretion
-H+ secretion
-Titration of urinary buffers
(And reabsorption of filtered buffer)
Total acid secretion 1-1.5meq/kg/day
Acid-Base: Physiology (6)
Since homeostatic mechanisms of body
cannot allow large changes in pH, acid
produced must be buffered.
BUFFERS: Weak acids which can release or
take up H+.
e.g. HCl + Na2HPO4
NaCl + NaH2PO4
NaOH + Na2HPO4
NaH2PO4 + H2O
Acid-Base: Physiology (7)
Bicarbonate system:
H2CO3
H+ + HCO3Most important system because:
• H2CO3
CO2
+ H2O
• HCO3- present in high concentrations
(24mM/l)
Acid-Base: Physiology (8)
Henderson-Hasselbalch Eqn:
pH = pK + log [HCO3]
[H2CO3]
= 6.1 + log [HCO3]
[0.03pCO2]
But Henderson Eqn. much more useful:
[H+] = 24 x pCO2
[HCO3-]
Relationship between pH and H+ Concentration in
the physiologic range
pH
H+, (nanomol/L)
7.8
7.7
7.6
7.5
7.4
7.3
7.2
7.1
7.0
6.9
6.8
16
20
26
32
40
50
63
80
100
125
160
Acid-Base: Physiology (9)
[H+] = 24 x pCO2
[HCO3]
e.g. 40 = 24 x 40
[HCO3]
[HCO3] = 24
pK = 6.1 (far from normal pH of 7.4). However,
this system is efficient because pCO2
controlled by ventilation
Acid-Base: Physiology (10)
ISOHYDRIC PRINCIPLE
All buffers in solution are in equilibrium:
[H+] = k1 [pCO2] = k2 [H2PO4]
[HCO3-]
[HPO42-]
= k3 [HA]
[ A -]
Thus, all extracellular buffers are consumed
at an equal rate
Acid-Base: Physiology (11)
Extracellular buffers:
Bicarbonate most important:
H2SO4 + 2NaHCO3
2H2O
Na2SO4 + H2CO3
HCO3- cannot buffer H2CO3:
H2CO3 + HCO3HCO3- + H2CO3
Thus, H2CO3 is buffered by intracellular buffers.
Other extracellular buffers:
•
HPO42- (1mM/l)
•
Plasma proteins: H+ + PrHPr
2CO2
+
Acid-Base: Physiology (12)
Intracellular and bone buffers:
Proteins, organic and inorganic phosphates, Hb in
erythrocytes:
H+ + HbHHb
Also HCO3 (12mmol/L)
Bone is important IC buffer (40% of buffering of acute
acid load)
Uptake of H+ in exchange for surface Na+ and K+, and
dissolution of bone mineral releasing NaHCO3 and
KHCO3, and then CaCO3 and CaHPO4.
Acid-Base: Physiology (13)
RESPONSE TO METABOLIC AND RESPIRATORY
ACID LOADS
•
Buffering by plasma HCO3- occurs immediately
•
Intracellular buffering of CO2 : 15mins
•
Entry of H+ into cells: 2-4h
Acid-Base: Physiology (14)
Buffering of CO2 is intracellular:
CO2 + H2O
H2CO3
CO2
HCO3- + H+
CO2 + H2O
H2CO3 + HbHHb + HCO3-
HCO3-
Acid-Base: Physiology (15)
RESPIRATORY COMPENSATION
In the case of metabolic acidosis:
pCO2 = 1.5HCO3- + 8
i.e. If HCO3- 14, expected pCO2 = (1.5 x 14) + 8
= 29
H+ = 24 x 29 = 50
pH = 7.3
14
If there were no change in pCO2:
H+ = 24 x 40 = 68.5 pH ~ 7.17
14
Thus: RESPIRATORY COMPENSATION VERY
IMPORTANT
Acid-Base: Physiology (16)
Buffering of acid-base loads:
1.
Chemical buffering
2.
Changes in ventilation to control pCO2
3.
Alterations in renal H+ excretion to regulate plasma [HCO3-].
Renal H+ excretion:
1.
Kidneys must excrete 50-100mM H+ generated each day
2.
All HCO3- filtered must be reabsorbed (since loss of HCO3from body is equivalent to adding H+.
3.
H+ secreted by proximal tubules and collecting tubules (by
different mechanisms).
4.
Daily acid load cannot be excreted as free acid, and thus
must be buffered in urine, by phosphate or NH3.
How to get rid of H+ ?
Solution: “proton acceptors”
Proton Acceptor #1: NH3
Glutamine
NH4+
Glutaminase
H+
Na+
H+
NH3
NH3
NH3 + CO2 + H2O
HCO3-
NH4+
Na+
NH4+
Proximal tubule
NH4+ undergoes counter-current
multiplication-1
NH4+
NH4+ undergoes counter-current
multiplication-2
H+
NH4+
H+
NH3
NH4+
NH3
NH4+
NH4+ undergoes counter-current
multiplication-3
NH3
NH3
Na+
NH4+
NH3
H+
NH3
ATP
H+
ADP + Pi
a IC cell
NH4+
Proton Acceptor #2: HPO4-urine
H+ + HPO4--  H2PO4-
pKa = 6.8
Consider 50 millimoles of
phosphate in the
glomerular filtrate:
Location
pH
HPO4--
H2PO4-
filtrate
7.4
40
10
0
end prox
6.8
25
25
15
urine
4.8
0.5
49.5
amt buffered
39.5
The Four Cardinal Acid Base Disorders
pCO2
[HCO3-]
Disorder
pH
M acidosis



M alkalosis



R acidosis



R alkalosis



Acid-Base Disorders (1)
Evaluation begins with pH: this indicates main disorder.
e.g. pH = 7.3 (H+= 50). HCO3- = 15 pCO2 = 30
H+ = 24 x pCO2 = 24 x 30 = 48
HCO315
i.e. Pure metabolic acidosis with respiratory compensation
But:
pH = 7.4 (H+= 40) HCO3-=14 pCO2= 23
The expected pCO2 for HCO3- of 14 would be (14 x 1.5 + 8) = 29.
Thus, this is a mixed metabolic acidosis and respiratory alkalosis,
e.g. salicylate poisoning.
Acid-Base Disorders (1) (Cont)
pH
= 7.35
pCO2 = 50
HCO3- = 27
This is a chronic respiratory acidosis with renal compensation
Compensatory changes never return pH to
normal. Thus, if pH is normal with
alterations in HCO3- and pCO2, a mixed
disorder is present.
Acid-Base Disorders (2)
Respiratory Acidosis
15,000mM CO2 produced every day
CO2 + H2O
H2CO3
HCO3- + H+
H+ combines with intracellular buffers:
H2CO3 + HbHHb + HCO3Thus, metabolically generated CO2 is carried in
bloodstream as HCO3-, with little change in pH.
Hypercapnia and respiratory acidosis usually due to
reduction in effective respiratory ventilation, not
increase in CO2 production. BUT:
Respiratory Acidosis
In conditions of hypovolemia, there is
reduced muscle blood flow, and thus
reduced clearance of CO2 from muscle.
Thus pCO2 rises and pH falls, without change
in respiration
Acid-Base Disorders (2)
Respiratory Acidosis
Compensation (slow, because it is renal)
• Acute: 1meq/l increase in HCO3 /10mmHg
rise in pCO2
• Chronic: 3.5meq/l increase in HCO3
/10mmHg rise in pCO2
Acid-Base Disorders (5)
Respiratory Alkalosis
Primary decrease in pCO2.
Compensation requires lowering of HCO3-.
H+ moves from cells into ECF:
H+ + HCO3H2CO3
CO2 + H2O
(H+ derived from HBuf
H+ + Buf -)
HCO3- falls 2meq/l for each 10mmHg fall in pCO2.
Chronic respiratory alkalosis
Compensatory decrease in renal H+ excretion which begins within
2h but is not complete for 2-3 days. Thus HCO3- falls 4meq/l
for each 10mmHg fall in pCO2.
Usually caused by primary hypoxemia, e.g. pulmonary disease,
CHF, severe anemia; or direct stimulation of respiratory
center: Gram Neg. sepsis, salicylate poisoning; mechanical
ventilation
Causes of Respiratory Alkalosis
Acute
Chronic
10 mm Hg  pCO2 
2 mEq/L  HCO3-
10 mm Hg  pCO2 
3-5 mEq/L  HCO3-
Fear
Altitude; Psychosis
Pain
Salicylates
Liver failure
Anxiety
Sepsis; Stiff lungs
Acid-base exams…
Pregnancy
Neurological
Iatrogenic (wrong
ventilator setting)
Acid-Base Disorders (6)
METABOLIC ACIDOSIS
Low pH, low HCO3- , compensatory hyperventilation.
HCO3- less than 10 always indicates metabolic acidosis, since
renal compensation for chronic hypercapnia cannot reduce
HCO3- to this extent.
H+ + HCO3H2CO3
CO2 + H2O
Thus metabolic acidosis can be produced by addition of H+ or
loss of HCO3-.
Buffering:
•
Extracellular buffering (HCO3-) very efficient.
•
Intracellular buffering: 55-60% of acid load.
K+ moves out of cells. Thus metabolic acidosis often associated
with hyperkalemia (0.6meq/l rise in K+ for every 0.1pH unit
fall in pH).
Does not occur in organic acidosis (lactic, ketosis).
Pathogenesis of Metabolic Acidosis
Acidosis-induced decrease in Bicarbonate
Acid production can be:
1. Normal
• Under-excretion of acid (acute or chronic renal
failure, renal tubular acidosis)
• Bicarbonate wasting (renal or GI)
2. Excessive
• Endogenous acid (lactic, ketone, amino, phophoric)
• Exogenous acid (salicylate, methanol, ethylene
glycol, HCl)
Acid-Base Disorders (7)
METABOLIC ACIDOSIS (cont)
Respiratory compensation is important in acute metabolic
acidosis, but not in chronic metabolic acidosis (fall in pCO2
reduces HCO3- reabsorption in kidney).
Renal buffering:
H+ + HPO42-
H2PO4-
H+ + NH3
NH4+
Decreased H+ excretion (e.g. CRF, RTA) causes slowly
developing acidosis. Acute increase in acid load can
overwhelm renal secretory capacity and cause rapid onset of
severe metabolic acidosis.
Acid-Base Disorders (8)
METABOLIC ACIDOSIS (cont)
ANION GAP
= [Na+] – ([Cl-] + [HCO3-])
= 140 – (105 + 24)
= 11
A.G. = 12 + 2
Usually caused by increase in unmeasured anions.
e.g. If acid is HCl:
HCl + NaHCO3
NaCl + H2CO3
CO2 + H2O
HCO3- replaced by HCl; thus no change in A.G.
If acid HA:
HA + NaHCO3
NaA + H2CO3
CO2 + H2O
Accumulation of A- (not usually measured) leads to increase in
A.G.
A.G.
UC 13
UA 25
Most important anion is Pr-. For every 1g reduction in serum
albumin, AG falls by 2.3mmol/l.
IgG cationic, IgA anionic
Acid-Base Disorders (9)
METABOLIC ACIDOSIS (cont)
A- usually lactate, ketones, HCOOH or (COOH)2.
e.g. A 27 year old diabetic presents in coma:
Na+ 140
pH
7.1
K+
7.0
pCO2 20
Cl105
HCO3- 6
Glucose 800
Ketones 4+
A.G. 29
Decrement in HCO3- =18
Increase in A.G. =18
Acid-Base Disorders (10)
METABOLIC ACIDOSIS (cont)
•
•
•
Loss of HCO3Thus: Normal A.G.
Anion Gap in renal failure:
Retention of H+,
SO42Thus: Raised A.G.
Anion Gap in Lactic Acidosis: Increased production
of Lactate-:
Thus, raised A.G.
Anion Gap in diarrhea:
ANION GAP
H+X- + NaHCO3 = Na+X- + CO2 + H2O
AG = Na+ + {Cl- + HCO3} = 12+2 mmol
NORMAL
Na+
140
Cl105
HCO3
25
AG
10
DHCO3
DAG
LACT.
DLACT.
(D = change from normal)
NORMAL
AG ACIDOSIS
140
115
15
10
-10
0
1
0
HIGH
AG ACIDOSIS
140
105
15
20
-10
10
10
+10
CAUSES OF KETOACIDOSIS
1. Starvation
4. Enzyme Deficiences
2. Diabetes Mellitus
-G-6 Phosphatase
3. Alcoholic
-F-1,6 Diphosphatase
5.False Positives
-Paraldehyde
-Antabuse + ETOH
-Captopril
-Isopropyl (rubbing alcohol)
DIAGNOSIS OF LACTIC ACIDOSIS
• HCO3, pCO2, pH: all low
• Anion gap increased > 12
• Ketotest Neg; BUN < 40mg/dl
• No intoxication
• Serum [lactate] increased > 2mM.
-------------------------------------------------------------------------------------------------CLINICAL EVALUATION OF TISSUE OXYGENATION:
• Type A: Clinically apparent hypoxia (cyanosis, hypotension, hypoxemia)
-CAUSES: CHF, SHOCK, ANEMIA, SEVERE HYPOXEMIA
• Type B: Clinically well oxygenated (pink periphery, normal BP)
-CAUSES:
a) Common: liver damage, sepsis, seizures, sepsis, DM, malignancy
b) Drugs & Toxins: Ethanol, methanol, biguanides
c) Hereditary disorders: von Gierke’s disease, pyruvate D-H def.
d) Miscellaneous: D-lactic acidosis
Uremia is indicated by BUN, creatinine
(chronicity by kidney size and Hct).
Methanol - presents with
± abdominal pain, vomiting,
headache; CT: BL putamen infarcts
visual disturbance (optic neuritis)
TOXIC ALCOHOLS
ETHANOL & LACTIC ACIDOSIS
TOXIC ALCOHOLS
Methanol intoxication: neurological effects
Normal retina (left); optic neuritis (right)
Putamen
infarcts
Ethylene glycol - presents with
± CNS disturbances,
cardiovascular collapse,
respiratory failure,
renal failure
Oxalate crystals
(octahedral or dumbell)
in urine are diagnostic
Anion gap may be > 50
Osmolal gap > 10 mOsm
NORMAL ANION GAP ACIDOSIS
2 Main Causes:
1. Diarrhea
2. Renal Tubular Acidosis
Diarrhea Causes Loss of HCO3And a Normal Anion Gap Acidosis
And Hypokalemia
Pancreas
Pancreas
HCO3-
HCO3-
Ileum
HCO3-
Cl-
Ileum
Cl-
Cl- Colon
Normal
K+
HCO3
Diarrhea
-
Colon
(TYPE IV)
Distal RTA
Na+
Na+
K+
K+
Auto-immune
Principal cell
Aldosterone
ATP
H+
HCO3-
ADP + Pi
Clamphotericin
Cl-
a IC cell
Cl-
Cl-
HCO3-
ATP
H+
ADP + Pi
b IC cell
Na+
Na+
K+
K+
Hypokalemia
in
distal RTA:
Principal cell
Aldosterone
ATP
H+
HCO3-
ADP + Pi
Cl-
+
H no
longer shunts
Na +
current so
K+ must
do so
Cl-
a IC cell
Cl-
Cl-
HCO3-
ATP
H+
ADP + Pi
b IC cell
Na+
Na+
K+
K+
Hyporeninhypo
aldosteronism
Principal cell
Aldosterone
ATP
H+
HCO3-
ADP + Pi
Cl-
Diabetes
is the main
cause
Cl-
a IC cell
Cl-
Cl-
HCO3-
ATP
H+
ADP + Pi
b IC cell
Hypoaldosteronism
(“Type IV RTA”)
Urine pH generally < 5.5
as if the H+ gradient is OK
but the H+ “throughput” is poor
Plasma [HCO3-] usually above 15 mEq/L
Major problem: hyperkalemia
suppresses ammoniagenesis
CAUSES OF METABOLIC
ALKALOSIS
VOLUME CONTRACTION
Vomiting, N/G suction
Renal loss of H+, Cl- and K+: diuretics, drug
anions.
VOLUME EXPANSION, HTN, K+DEFICIENCY
High renin (RAS)
Low renin (Primary hyperaldosteronism)
GASTRIC JUICE
Vomitus/Gastric drainage:
Volume: 0.00 to 3.00 L/d
Na+:
20 to 100 mmol/L
K +:
10 to 15 mmol/L
Cl-:
120 to 160 mmol/L
PATHOPHYSIOLOGY: PHASES OF
METABOLIC ALKALOSIS DUE TO
VOMITING
 GENERATIVE PHASE
LOSS OF ACID
GAIN OF HCO3LOSS OF Cl MAINTENANCE PHASE (KIDNEY LOSES ABILITY TO
EXCRETE HCO3- EFFICIENTLY)
VOLUME CONTRACTION
LOW GFR
Cl- DEPLETION
K+ DEPLETION
SYNDROME OF ECF CONTRACTION,
NORMAL BP, K+ DEFICIENCY &
SECONDARY HYPERALDOSTERONISM
 GI ORIGIN
VOMITING & NG SUCTION
VILLOUS ADENOMA
 RENAL ORIGIN
DIURETICS, EDEMATOUS STATES
K+ DEPLETION
BARTTER & GITELMAN SYNDROME
NON-REABSORBABLE ANIONS (PENICILLIN &
CARBENICILLIN)
Na+
Na+
K+
K+
Principal cell
ATP
Collecting
Duct
Acidification
H+
HCO3-
ADP + Pi
ClCl-
a IC cell
Cl-
Cl-
HCO3-
ATP
H+
pHmin = 5
ADP + Pi
b IC cell
‫)‪PROBLEMS IN ACID-BASE (1‬‬
‫אשה בת ‪ 35‬מגיעה לחדר מיון מחוסרת הכרה‪ .‬התלוננה על חולשה הולכת וגוברת במשל‬
‫חודשיים‪ .‬בבדיקה‪ :‬ירידה בהחזרים גידיים‪.‬‬
‫‪Na‬‬
‫‪135meq/L‬‬
‫‪K‬‬
‫‪1.5meq/L‬‬
‫‪Cl‬‬
‫‪118meq/L‬‬
‫‪HCO3‬‬
‫‪7‬‬
‫‪Anion Gap‬‬
‫‪10meq/L‬‬
‫‪pH‬‬
‫)‪6.88 (H+ 132‬‬
‫‪pCO2 40‬‬
‫‪ABG:‬‬
‫‪pH‬‬
‫‪Urine:‬‬
‫‪6.5‬‬
‫)‪PROBLEMS IN ACID-BASE (2‬‬
‫אשה בת ‪ 68‬מגיעה לחדר מיון לאחר שלשולים במשך שבוע ימים‪ .‬משקל גוף ‪ 60‬ק''ג‪.‬‬
‫לחץ דם ‪ 100/60‬פרקדן‪ 70/40 ,‬בעמידה‪ .‬ירידה ניכרת בטורגור של העור‪.‬‬
‫‪Creatinine‬‬
‫‪3.5mg/dl‬‬
‫‪Na‬‬
‫‪133meq/L‬‬
‫‪K‬‬
‫‪2.5meq/L‬‬
‫‪Cl‬‬
‫‪118meq/L‬‬
‫‪HCO3‬‬
‫‪5‬‬
‫‪Anion Gap‬‬
‫‪10meq/L‬‬
‫‪12‬‬
‫‪57neq/L‬‬
‫‪7.24‬‬
‫‪pCO2‬‬
‫‪H+‬‬
‫‪pH‬‬
‫‪ABG:‬‬
PROBLEMS IN ACID-BASE (3)
,120.80 ‫ לחץ דם‬:‫ בבדיקה‬.‫ ימים‬5 ‫ אושפז בבי''ח עקב הקאות במשך‬36 ‫אלכוהוליסט בן‬
.‫ערפול הכרה‬
Urea
80mg/dl
Creatinine
1.9mg/dl
Na
135meq/L
K
5.2meq/L
Cl
85meq/L
HCO3
25meq/L
Anion Gap
25meq/L
Ketones:
Weakly Positive
ABG:
pCO2 40
H+
40 (pH 7.4)
‫)‪PROBLEMS IN ACID-BASE (4‬‬
‫אצל אשה בת ‪ ,47‬בד''כ בבריאות טובה‪ ,‬נמצאת ‪ K‬של ‪ .3.0‬ללא אנמנזה של יתר לחץ‬
‫דם‪ ,‬הקאות או שימוש בדיורטיקה‪ .‬קיבלה תוספות של ‪ ,K‬אך היפוקלמיה חזרה כאשר‬
‫התוספות הופסקו‪ .‬אושפזה לשם בירור‪ .‬בדיקה פיזיקלית‪ :‬ב‪.‬מ‪.‬פ‪ .‬לחץ דם תקין‪.‬‬
‫‪Urea‬‬
‫‪30mg/dl‬‬
‫‪Creatinine‬‬
‫‪0.8mg/dl‬‬
‫‪Na‬‬
‫‪142meq/L‬‬
‫‪K‬‬
‫‪2.7meq/L‬‬
‫‪Cl‬‬
‫‪98meq/L‬‬
‫‪HCO3‬‬
‫‪34meq/L‬‬
‫‪Anion Gap‬‬
‫‪10meq/L‬‬
‫‪(Renin:‬‬
‫)‪High‬‬
‫)‪(Aldosterone: High‬‬
‫‪85meq‬‬
‫‪85meq‬‬
‫‪65meq‬‬
‫‪Na‬‬
‫‪K‬‬
‫‪Cl‬‬
‫‪24h Urinary Excretion:‬‬
PROBLEMS IN ACID-BASE (5)
.‫ לא ניתן לקבל אנמנזה‬.‫ חולשה וירידה בהחזרים‬,‫ אושפזה בבי''ח עקב בלבול‬74 ‫אשה בת‬
Urea
Creatinine
Na
K
Cl
HCO3
Anion Gap
76mg/dl
1.6mg/dl
145meq/L
2.4meq/L
86meq/L
45meq/L
14meq/L
24h Urinary Excretion:
Na
K
Cl
pCO2
H+
ABG:
30meq
65meq
2meq
49
26 (pH 7.58)