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ACID-BASE-ACID-BASE-CLINICAL PHYSIOLOGYCLINICAL PHYSIOLOGY
Jayson RapoportJayson RapoportFaculty of Medicine ,
Hebrew University, JerusalemDepartment of Nephrology ,
Kaplan Medical Center, Rehovot
Acid-Base: Physiology (1)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 pHpHpH = -log [H+]
= -log [40 x 10-9] = 7.4
Acid-Base: Physiology (2)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)Acid-Base: Physiology (3)
Definitions:
ACIDACID: substance that donates H+
BASEBASE: substance that accepts H+
ACID BASEH2CO3 H+ + HCO3
-
HCl H+ + Cl-
NH4+ H+ + NH3
Acid-Base: Physiology (4)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)Acid-Base: Physiology (6)
Since homeostatic mechanisms of body cannot allow large changes in pH, acid produced must be buffered.
BUFFERS:BUFFERS: Weak acids which can release or take up H+.
e.g. HCl + Na2HPO4 NaCl + NaH2PO4
NaOH + Na2HPO4 NaH2PO4 + H2O
Acid-Base: Physiology (7)Acid-Base: Physiology (7)
Bicarbonate system:H2CO3 H+ + HCO3
-
Most important system because:
• H2CO3 CO2 + H2O
• HCO3- present in high concentrations
(24mM/l)
Acid-Base: Physiology (8)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)
7.8 167.7 207.6 267.5 327.4 407.3 507.2 637.1 807.0 1006.9 1256.8 160
Acid-Base: Physiology (9)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)Acid-Base: Physiology (10)
ISOHYDRIC PRINCIPLE
All buffers in solution are in equilibrium:
[H+] = k1 [pCO2] = k2 [H2PO4] = k3 [HA]
[HCO3-] [HPO4
2-] [ A-]
Thus, all extracellular buffers are consumed at an equal rate
Acid-Base: Physiology (11)Acid-Base: Physiology (11)
Extracellular buffers:Bicarbonate most important:H2SO4 + 2NaHCO3 Na2SO4 + H2CO3 2CO2
+ 2H2O
HCO3- cannot buffer H2CO3:
H2CO3 + HCO3- HCO3
- + H2CO3
Thus, H2CO3 is buffered by intracellular buffers.
Other extracellular buffers:
• HPO42- (1mM/l)
• Plasma proteins: H+ + Pr- HPr
Acid-Base: Physiology (12)Acid-Base: Physiology (12)
Intracellular and bone buffers:Proteins, organic and inorganic phosphates, Hb in
erythrocytes:H+ + Hb- HHb
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)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)Acid-Base: Physiology (14)
Buffering of CO2 is intracellular:
CO2 + H2O H2CO3 HCO3- + H+
CO2 CO2 + H2O
H2CO3 + Hb-
HHb + HCO3
- HCO3-
Acid-Base: Physiology (15)Acid-Base: Physiology (15)
RESPIRATORY COMPENSATIONIn the case of metabolic acidosis:pCO2 = 1.5HCO3
- + 8i.e. If HCO3
- 14, expected pCO2 = (1.5 x 14) + 8 = 29
H+ = 24 x 29 = 50 pH = 7.3 14If there were no change in pCO2:H+ = 24 x 40 = 68.5 pH ~ 7.17 14Thus: RESPIRATORY COMPENSATION VERY
IMPORTANT
Acid-Base: Physiology (16)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 HCO3
- from 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.
NH4+
NH4+
Na+
Solution: “proton acceptors”Proton Acceptor #1: NH3
H+H+
Na+
NH3NH3
NH4+
HCO3-
Glutamine NH3 + CO2 + H2O
Glutaminase
Proximal tubule
How to get rid of H+ ?
NH4+
NH4+ undergoes counter-current
multiplication-1
NH4+
NH3
NH3
H+H+
NH4+ undergoes counter-current
multiplication-2
NH4+
NH4+
IC cell
Na+
H+
ATP
ADP + Pi
NH3NH3
NH4+
NH4+
H+
NH3
NH3
NH4+ undergoes counter-current
multiplication-3
Proton Acceptor #2: HPO4--
urine H+ + HPO4-- H2PO4
- pKa = 6.8
Location pH HPO4-- H2PO4
- amt buffered
Consider 50 millimoles of phosphate in the glomerular filtrate:
filtrate 7.4 40 10 0
end prox 6.8 25 25 15
urine 4.8 0.5 49.5 39.5
The Four Cardinal Acid Base Disorders
M acidosis
M alkalosis
R acidosis
R alkalosis
Disorder pH pCO2 [HCO3-]
Acid-Base Disorders (1)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
HCO3- 15
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)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)Acid-Base Disorders (2)
Respiratory Acidosis15,000mM CO2 produced every day
CO2 + H2O H2CO3 HCO3- + H+
H+ combines with intracellular buffers:
H2CO3 + Hb- HHb + HCO3-
Thus, 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 AcidosisIn 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)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)Acid-Base Disorders (5)
Respiratory AlkalosisPrimary decrease in pCO2. Compensation requires lowering of HCO3
-.H+ moves from cells into ECF:H+ + HCO3
- H2CO3 CO2 + H2O(H+ derived from HBuf H+ + Buf -)HCO3
- falls 2meq/l for each 10mmHg fall in pCO2.Chronic respiratory alkalosisCompensatory 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
Chronic
10 mm Hg pCO2 3-5 mEq/L HCO3
-
Acute
10 mm Hg pCO2 2 mEq/L HCO3
-
Fear
Pain
Acid-base exams…
Anxiety
Altitude; Psychosis
Sepsis; Stiff lungs
Liver failure
Salicylates
Pregnancy
Neurological
Iatrogenic (wrongventilator setting)
Acid-Base Disorders (6)Acid-Base Disorders (6)
METABOLIC ACIDOSISMETABOLIC ACIDOSISLow 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+ + HCO3
- H2CO3 CO2 + H2OThus 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 BicarbonateAcid 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)Acid-Base Disorders (7)
METABOLIC ACIDOSIS (cont)METABOLIC ACIDOSIS (cont)Respiratory compensationRespiratory compensation is important in acute metabolic is important in acute metabolic
acidosis, but not in chronic metabolic acidosis (fall in pCOacidosis, but not in chronic metabolic acidosis (fall in pCO22 reduces 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)Acid-Base Disorders (8)
METABOLIC ACIDOSIS (cont)METABOLIC ACIDOSIS (cont)ANION GAPANION GAP
A.G. A.G. = [Na= [Na++] – ([Cl] – ([Cl--] + [HCO + [HCO33--])])
= 140 – (105 + 24)= 140 – (105 + 24)= 11= 11
A.G. = 12 A.G. = 12 ++ 2 2Usually caused by increase in unmeasured anions.Usually caused by increase in unmeasured anions.e.g. If acid is HCl:e.g. If acid is HCl:
HCl + NaHCOHCl + NaHCO33 NaCl + HNaCl + H22COCO33 CO CO22 + H + H22OO
HCOHCO33-- replaced by HCl; thus replaced by HCl; thus nono change in A.G. change in A.G.
If acid HA:If acid HA:
HA + NaHCOHA + NaHCO33 NaA + HNaA + H22COCO33 CO CO22 + H + H22OO
Accumulation of AAccumulation of A-- (not usually measured) leads to increase in (not usually measured) leads to increase in A.G.A.G.
Most important anion is Pr-. For every 1g reduction in serum
albumin, AG falls by 2.3mmol/l. IgG cationic, IgA anionic
UC 13 UA 25
Acid-Base Disorders (9)Acid-Base Disorders (9)
METABOLIC ACIDOSIS (cont)METABOLIC ACIDOSIS (cont)AA-- usually lactate, ketones, HCOOH or (COOH) usually lactate, ketones, HCOOH or (COOH)22.
e.g. A 27 year old diabetic presents in coma:
Na+ 140 pH 7.1
K+ 7.0 pCO2 20
Cl- 105 HCO3- 6
Glucose 800 Ketones 4+
A.G. 29
Decrement in HCO3- =18
Increase in A.G. =18
Acid-Base Disorders (10)Acid-Base Disorders (10)
METABOLIC ACIDOSIS (cont)
• Anion Gap in diarrhea: Loss of HCO3-
Thus: Normal A.G.• Anion Gap in renal failure: Retention of H+,
SO42-
Thus: Raised A.G.• Anion Gap in Lactic Acidosis: Increased
production of Lactate-: Thus, raised
A.G.
ANION GAP
H+X- + NaHCO3 = Na+X- + CO2 + H2O
AG = Na+ + {Cl- + HCO3} = 12+2 mmol
NORMAL NORMAL HIGH
AG ACIDOSIS AG ACIDOSIS
Na+ 140 140 140
Cl- 105 115 105
HCO3 25 15 15
AG 10 10 20
HCO3 -10 -10
AG 0 10
LACT. 1 10
LACT. 0 +10
(D = change from normal)
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 infarctsvisual disturbance (optic neuritis)
TOXIC ALCOHOLS
ETHANOL & LACTIC ACIDOSIS
TOXIC ALCOHOLS
Normal retina (left); optic neuritis (right)
Methanol intoxication: neurological effects
Putameninfarcts
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
Pancreas
Ileum
Colon
Pancreas
Ileum
Colon
Diarrhea Causes Loss of HCO3-
And a Normal Anion Gap AcidosisAnd Hypokalemia
HCO3-
HCO3-
Cl-
HCO3-
Cl-
K+ HCO3-
Normal Diarrhea
Cl-
(TYPE IV)(TYPE IV)
Distal RTA
Na+
K+
Na+
K+
Principal cell
IC cell
IC cell
HCO3-
Cl-
HCO3-
Cl-
Cl-
H+
ATP
ADP + Pi
H+
ATP
ADP + Pi
Cl-
Aldosterone
amphotericin
Auto-immune
Hypo-kalemia
indistal RTA:
H + nolonger shunts
Na +
current soK+ must
do so
Na+
K+
Na+
K+
Principal cell
IC cell
IC cell
HCO3-
Cl-
HCO3-
Cl-
Cl-
H+
ATP
ADP + Pi
H+
ATP
ADP + Pi
Cl-
Aldosterone
Hyporenin-hypo
aldosteronism
Na+
K+
Na+
K+
Principal cell
IC cell
IC cell
HCO3-
Cl-
HCO3-
Cl-
Cl-
H+
ATP
ADP + Pi
H+
ATP
ADP + Pi
Cl-
Aldosterone
Diabetesis the maincause
Urine pH generally < 5.5as if the H+ gradient is OK but the H+ “throughput” is poor
Plasma [HCO3-] usually above 15 mEq/L
Major problem: hyperkalemiasuppresses ammoniagenesis
Hypoaldosteronism(“Type IV RTA”)
CAUSES OF METABOLIC ALKALOSIS
VOLUME CONTRACTIONVomiting, N/G suctionRenal loss of H+, Cl- and K+: diuretics, drug
anions.
VOLUME EXPANSION, HTN, K+-DEFICIENCYHigh 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 PHASELOSS OF ACIDGAIN OF HCO3
-
LOSS OF Cl-
MAINTENANCE PHASE (KIDNEY LOSES ABILITY TO EXCRETE HCO3
- EFFICIENTLY)VOLUME CONTRACTIONLOW GFRCl- DEPLETIONK+ DEPLETION
SYNDROME OF ECF CONTRACTION, NORMAL BP, K+ DEFICIENCY &
SECONDARY HYPERALDOSTERONISM
GI ORIGINVOMITING & NG SUCTIONVILLOUS ADENOMA
RENAL ORIGINDIURETICS, EDEMATOUS STATESK+ DEPLETIONBARTTER & GITELMAN SYNDROMENON-REABSORBABLE ANIONS (PENICILLIN &
CARBENICILLIN)
CollectingDuct
Acidification
Na+
K+
Na+
K+
Principal cell
IC cell
IC cell
HCO3-
Cl-
HCO3-
Cl-
Cl-
H+
ATP
ADP + Pi
H+
ATP
ADP + Pi
Cl-
pHmin = 5
PROBLEMS IN ACID-BASE (1)
מגיעה לחדר מיון מחוסרת הכרה. התלוננה על חולשה הולכת 35אשה בת וגוברת במשל חודשיים. בבדיקה: ירידה בהחזרים גידיים.
Na 135meq/L
K 1.5meq/L
Cl 118meq/L
HCO3 7
Anion Gap 10meq/L
ABG: pH 6.88 (H+ 132)
pCO2 40
Urine: pH 6.5
PROBLEMS IN ACID-BASE (2)
מגיעה לחדר מיון לאחר שלשולים במשך שבוע ימים. משקל גוף 68אשה בת בעמידה. ירידה ניכרת בטורגור של 70/40 פרקדן, 100/60 ק''ג. לחץ דם 60
העור.
Creatinine 3.5mg/dl
Na 133meq/L
K 2.5meq/L
Cl 118meq/L
HCO3 5
Anion Gap 10meq/L
ABG: pCO2 12
H+ 57neq/L
pH 7.24
PROBLEMS IN ACID-BASE (3)
ימים. בבדיקה: לחץ דם 5 אושפז בבי''ח עקב הקאות במשך 36אלכוהוליסט בן , ערפול הכרה.120.80
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)
. ללא אנמנזה של יתר 3.0 של K, בד''כ בבריאות טובה, נמצאת 47אצל אשה בת , אך היפוקלמיה Kלחץ דם, הקאות או שימוש בדיורטיקה. קיבלה תוספות של
חזרה כאשר התוספות הופסקו. אושפזה לשם בירור. בדיקה פיזיקלית: ב.מ.פ. לחץ דם תקין.
Urea 30mg/dlCreatinine 0.8mg/dlNa 142meq/LK 2.7meq/LCl 98meq/LHCO3 34meq/LAnion Gap 10meq/L
24h Urinary Excretion: Na 85meq (Renin: High)K 85meq (Aldosterone: High)Cl 65meq
PROBLEMS IN ACID-BASE (5)
אושפזה בבי''ח עקב בלבול, חולשה וירידה בהחזרים. לא ניתן לקבל 74אשה בת אנמנזה.
Urea 76mg/dl
Creatinine 1.6mg/dl
Na 145meq/L
K 2.4meq/L
Cl 86meq/L
HCO3 45meq/L
Anion Gap 14meq/L
24h Urinary Excretion: Na 30meqK 65meqCl 2meq
ABG: pCO2 49
H+ 26 (pH 7.58)
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