ACID-BASE- CLINICAL PHYSIOLOGY Jayson Rapoport Faculty of Medicine, Hebrew University, Jerusalem Department of Nephrology, Kaplan Medical Center, Rehovot

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


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


Definitions:

ACIDACID: substance that donates H+

BASEBASE: substance that accepts H+

ACID BASEH2CO3 H+ + HCO3

-

HCl H+ + Cl-

NH4+ H+ + NH3


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


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


Bicarbonate system:H2CO3 H+ + HCO3

-

Most important system because:

• H2CO3 CO2 + H2O

• HCO3- present in high concentrations

(24mM/l)


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


[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


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


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


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.


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


Buffering of CO2 is intracellular:

CO2 + H2O H2CO3 HCO3- + H+

CO2 CO2 + H2O

H2CO3 + Hb-

HHb + HCO3

- HCO3-


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


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+


multiplication-2

NH4+

NH4+

IC cell

Na+

H+

ATP

ADP + Pi

NH3NH3

NH4+

NH4+

H+

NH3

NH3


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.


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


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


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)


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)


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.


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


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


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


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


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)


. 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


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)

Documents

ACID-BASE- CLINICAL PHYSIOLOGY Jayson Rapoport Faculty of Medicine, Hebrew University, Jerusalem Department of Nephrology, Kaplan Medical Center, Rehovot