Metabolic Acid Base Disturbances

Metabolic Acid-Base Disorders(An overview of etiology, pathophysiology and treatment.)

By:Omaid Hayat KhanPharm-D, MS (Clinical Pharmacy)Universiti Sains Malaysia.

An Overview of Kidney Regulates fluid volume and acid base balance of the plasma (pH 7.4) Excrete nitrogenous waste Synthesize erythropoietin, 1,25-dihydroxycholecalceferol & Renin Drug metabolism Is a target organ for both Parathormone (PTH) & Aldosterone.

Renal Corpuscular Region of a Nephron

A – Renal corpuscleB – Proximal tubuleC – Distal convoluted tubuleD – Juxtaglomerular apparatus1. Basement membrane (Basal lamina)2. Bowman's capsule – parietal layer3. Bowman's capsule – visceral layer3a. Pedicels (Foot processes from podocytes)3b. Podocyte

4. Bowman's space (urinary space)5a. Mesangium – Intraglomerular cell5b. Mesangium – Extraglomerular cell6. Granular cells (Juxtaglomerular cells)7. Macula densa8. Myocytes (smooth muscle)9. Afferent arteriole10. Glomerulus Capillaries11. Efferent arteriole

Classification of Acid Base Disorder

ACIDOSIS ALKALOSIS7.4

7.35 – 7.45

• -emia refers to a pH in blood• -osis refers to an abnormal condition or process

Plasma Buffer System

H+ + HCO3- H2CO3 CO2 + H2O

(Volatile Acid)

• Resisting to change in pH is very crucial for normal body functioning.

• Buffering refers to ability of solution to MAINTAIN / RESIST CHANGE in pH after addition of strong acid/alkali.

• Three general mechanism work together:1. Chemical buffering

• HCO3 in ECF• Proteins & phosphate buffers in ICF

2. Alveolar ventilation (maintaining PaCO2)

3. Renal H+ handling• HCO3 reabsorption• Excretion of titratable acid (H2PO4-) and NH4+

Plasma Buffer System

H+ + HCO3- H2CO3 CO2 + H2O

(Volatile Acid)

• Body’s principle extracellular buffer system is the carbonic acid/ bicarbonate system (H2CO3/HCO3

-) system.• Ratio of HCO3/H2CO3 is 20:1 which is constant at normal

pH.• Body’s main Acid = CO2

• If 1 HCO3 is lost from body 1 H+ stay behind, the net result is addition of 1 free H+ into the ECF.

• Conversely, if H+ is lost 1 HCO3 is added to the body.

Normal RangesBlood Gas Arterial Blood

pH 7.40 (7.35 – 7.45)

PaO2 80-100 mmHg

SaO2 95%

PCO2 35 – 45 mmHg

HCO3- 22 – 26 mEq/L (22-26 mmol/L)

WHEN TO ORDER ABGs???• Any serious illness• Multi-organ Failure• Respiratory Failure• Cardiac Failure• Uncontrolled DM (DKA)• Poisoning (Barbiturates, Ethylene glycol)

Classification of Acid/Base Disorders

Acidosis

(Fall in pH)

• Respiratory acidosis

• Metabolic Acidosis

Alkalosis

(Rise in pH)

• Respiratory acidosis

• Metabolic alkalosis

Can occur individually or together as compensatory response.

RESPIRATORY DISTURBANCESCaused by:

Altered alveolar ventilation Producing changes in arterial PaCO2 tension

Main culprit is CARBON DIOXIDE.

Increase in PaCO2 = AcidosisDecrease in PaCO2 = Alkalosis

METABOLIC DISTURBANCESCaused by:

Kidney Failure DKA Lactic acidosis Diarrhea/ Vomiting Starvation Poisoning Hypokalemia etc.

Main Culprit is BICARBONATE

Increase in HCO3 = AlkalosisDecrease in HCO3 = Acidosis

METABOLIC ACIDOSIS

METABOLIC ACIDOSISDecrease in pH…………..Decrease in HCO3-

Causes: Adding organic acid to ECF (Lactic acids, Keto Acids etc) Loss of HCO3- Stores (Diarrhea) Accumulation of endogenous acids due to impaired renal function. (eg.

Phosphates and sulphates) Serum ANION GAP (SAG) used to calculate the cause.

Elevated AG acidosis Normal AG acidosis

Primary Compensatory mechanism: Decreasing PaCO2 via hyperventilation (Kussmaul respiration as in DKA)

Clinical Presentation: Bone demineralization (rickets, osteomalacia, osteopenia) Acute manifestations of acute disease invlove CVS, Respo & CNS.

ANION GAP “Quantity of anions not balanced by cations.” Measurable Ions:

Major cation is Na+ and K+ Major Anions are HCO3- & Cl-

Unmeasurable Ions: Major cations are Ca++, Mg++, gamma globulins and K+ Major anions are Albumins, sulphate, phosphate,lactate and other organic

anions. Normal physiology: number of anion = number of cations So,

[Na] + [K] + Unmeasured cations = [Cl-] + [HCO3-] + Unmeasured anions ([Na] + [K] + Unmeasured cations ) – ([Cl-] + [HCO3-] + Unmeasured anions) = 0

But actual value is 12 mEq/L = WHY??? Hence there is a GAP and it is ANIONIC…. Why??

Practically Calculated as:

ANION GAP = [Na+] – ( [Cl-] + [HCO3-] )

Normal Value12 ± 4 mEq/L

Interpretation of ANION GAP


Case 1: HCl + NaHCO3 → NaCl + H2CO3 → CO2 + H2O

Case 2:

HA + NaHCO3 → NaA + H2CO3 → CO2 + H2O,

where A- is the unmeasured anion.


Causes of ELEVATED Anion Gap: remembered by the mnemonic KULT or the popular MUDPILERS

M = Methanol U = UremiaD = DKA (also AKA and starvation) P = ParaldehydeI = INHL = Lactic acidosis E = Ethylene GlycolR = Rhabdomyolysis / Renal failureS = Salycilates

K = Ketoacidosis (DKA,alcoholic ketoacidosis, starvation) U = Uremia (Renal Failure) L =Lactic acidosis T = Toxins (Ethylene glycol, methanol,

paraldehyde, salicylate)


Because, negatively charged plasma proteins account for the normal anion gap, the normal values should be adjusted downward for patients with hypoalbuminemia.

The approximate correction is a reduction in the normal anion gap of 2.5 meq/l for every 1g/dl decline in the plasma albumin concentration (normal value = 4 g/dl).

Interpretation of ANION GAP EXAMPLE:

A 60 year old homeless man presents with nausea, vomiting and poor oral intake 2 days prior to admission. The patient reports a 3 day history of binge drinking prior to symptoms.

Does the patient have an abnormal anion gap?

LABs Value Normal LABs Value Normal

Na 132 135 – 145 BUN 25 10 – 25

K 5 3.5 – 5 Cr 1.3 1.2 – 1.5

Cl 104 95 – 105 Glu 75 60 – 100

HCO3 16 22 – 26 pH 7.30 7.35 – 7.45

pCO2 29 35 – 45 PO2 92 80 – 100

Albumin 1.0 3.5 – 5


Is patient Acedemic Or Alkalemic? Acidemic. With low HCO3 and low pH. Hence METABOLIC ACIDOSIS.

Which type? Normal Anion gap OR Elevated Anion gap(Lactic or Ketoacidosis) ??

To find out calculate AG Anion gap = (Na-(Cl +HCO3-) = 132 -(104 +16) = 12 Lactic acidosis appears unlikely!!

However, note patient is severe hypoalbumenic. What is your inference? False anion gap which needs to be adjusted.

Therefore in this scenario, AG should be: Decline in albumin = 4 – 1 = 3 g/dL Reduction in normal anioin gap = 3 x 2.5 = 7.5 Adjusted anion gap = 12 -7.5 = 4.5

So what is your assessment now?? Patients has an elevated anion gap metabolic acidosis which may be due to lactic or ketoacidosis.


Na 132 135 – 145 BUN 25 10 – 25

K 5 3.5 – 5 Cr 1.3 1.2 – 1.5

Cl 104 95 – 105 Glu 75 60 – 100

HCO3 16 22 – 26 pH 7.30 7.35 – 7.45

pCO2 29 35 – 45 PO2 92 80 – 100

Albumin 1.0 3.5 – 5

HIGH ANION GAP METABOLIC ACIDOSIS

Decreased acid secretion

• Renal Failure

Increased acid production

• Lactic acidosis• Ketoacidosis

Toxicity

• Salicylate• Methanol

NORMAL ANION GAP METABOLIC ACIDOSIS

ORHYPERCHLOREMIC ANION GAP

Loss of HCO3 and Cations

• Diarrhoea

Impaired acidification of

urine

• RTA Type 1, 2 & 4

Difference in RTA types

Getting Rid of H+ (Acid Load)by Kidneys

Hydrogen ion secretion In form of non-volatile acids (as NH4 or titratable acids like H2PO4)

Normally, kidneys reabsorb all the filtered bicarbonate which is vitally important to maintain acid/base balance.

Bicarb. Reabsorption mainly occurs in proximal tubule (90%). Remaining occurs in thick ascending limb and collecting tubule.

1

2

3

45

6 7

Aldosterone

Getting Rid of H+ (Acid Load)by Kidneys

Excretion of titratable acids is dependent on the quantity of phosphate filtered and excreted by the kidneys, which is dependent on one's diet, and also PTH levels.

As such, the excretion of titratable acids is not regulated by acid base balance and cannot be easily increased to excrete the daily acid load.

Ammonium production can however be regulated to respond to acid base status

Getting rid of H+

1) NH4 production

2) Phosphate buffer

• 2 possible mechanisms.

• Depends on acid/base balance• Further produces HCO3 ions.

• Independent of acid base balance• Depends on ones diet and PTH

Ammonium Excretion 3 steps.

1. Ammonium Formation (ammoniagenesis) (proximal tubule)

2. Ammonium Reabsorption (Medullary Recycling)(thick ascending loop)

3. Ammonium Trapping (collecting tubule)

Note that this process is primarily dependent on acidification of the urine in the collecting tubule as a result of hydrogen secretion by intercalated cells.In states of alkalosis, the process is appropriately hindered as a result of the alkalemic urine.

Renal Acid Exretion; Take Home Points1. The net quantity of H+ ions excreted in the urine is equal to the amount of H+ excreted as

titratable acidity and NH4+ minus any H+ added to the body because of urinary HCO3- loss.

Net acid excretion(NAE) = titratable acidity + NH4+ - urinary HCO3

-

Note that normally there is no urinary HCO3- and therefore: Net acid excretion(NAE) = titratable acidity + NH4

+

2. Titratable acidity is dependent on the dietary intake of phosphate and cannot be regulated to increase acid excretion

3. The kidney 's main response to an increased acid load is to increase ammonium production and excretion

4. A very important feature of titrable acidity and ammonium excretion is the regeneration of bicarbonate ions.

5. The kidney must reabsorb all filtered HCO3- in order to maintain acid base balance.

6. Hydrogen ion secretion in the collecting tubule is very important in maximally acidifying the urine.

7. In states of acidosis, maximal acidification of the urine in the collecting tubule must occur for adequate ammonium excretion.

8. In states of acidosis, ammonium excretion is increased by increasing ammonium production and increased hydrogen ion secretion in the collecting duct.

9. Aldosterone stimulates secretion of hydrogen ion in the collecting duct .

10. Although the extracellular pH is the primary physiologic regulator of net acid excretion, in pathophysiologic states, the effective circulating volume, Aldosterone, and the plasma K+ concentration all can affect acid excretion, independent of the systemic pH.

METABOLIC ALKALOSIS

METABOLIC ALKALOSISIncrease in pH…………..Increase in HCO3-

Causes: Loss of H+ from GIT (nasogastric suctioning, Vomiting) Transcellular H+ shift (Hypokalemia) Loss of H+ from kidneyso Loop & thiazide Diureticso Mineralocorticoid excess (Cushing’s syndrome, Steroids)

Gain of HCO3 (Admin. Of bicarb. , Lactate, or citrate, Antacids) Contraction Alkalosis (reduction in ECV) Fail to excrete excess HCO3 (Abnormal renal function) Hypokalemia

Primary Compensatory mechanism: Increasing PaCO2 via hypoventilation. Increase excretion of HCO3 and conservation of H+ (Secondary)

Clinical Presentation: Often accompanied by Hypochloremia and Hypokalemia. No signs and symptoms associated with mild to moderate metabolic alkalosis. Severe is associated with cardiac arrhythmias (probably secondary to hypokalemia) and

neuromuscular irritability.

Generation(Initating factors)

Maintainance

METABOLIC ALKALOSIS

K+


MAINTAINANCE OF METABOLIC ALKALOSIS

Kidneys have a high rate of filtering / compensating excess HCO3

So normally, alkalosis is quickly compensated unless there is maintenance.

CAUSE 1: Vomiting >> decrease in ECV >>Decreased GFR (less HCO3 filtered) >> Increase angiotensin

& aldosterone >> Increase Na & HCO3 reabsorption >> Increased H+ secretion (via Na-H exchanger at proximal tubule) combined with filtered HCO3 leading to further

reabsorption >> Rise in plasma HCO3 >>Hypokalemic metabolic alkalosis Because Aldosterone primarily acts distally to increase H+ and K

secretion resulting in increased acid and potassium excretion.

MAINTAINANCE OF METABOLIC ALKALOSIS

CAUSE 2: Contraction Alkalosis Diuretics >> decrease ECV >> increase HCO3 >> compensation by release of H+ buffers

>> Normalized. However, if ECV reduction by diuretics result in hypovolemia >> Angiotensin & Aldosterone

stimulated >> & so on.. Increase HCO3 absorption & increase H & K secretion.>> Hypokalemia >> further maintains alkalosis.

CAUSE 3: Hypokalemia Commonly associated due to 2 factors:

1. Common causes of alkalosis leads to increase in aldosterone & thus cause hypokalemia

2. Hypokalemia itself is a cause of metabolic alkalosis. Hypokalemia cause alkalosis by 3 mechanisms:

1. Initially transcellular shifting throughout body

2. Transcellular shift in cells of proximal tubules Resulting in intracellular acidosis >> NH3 production >> Excretion

3. H+ secretion in proximal & distal tubules increase Leading to further reabsorption of HCO3

The net effect is an increase in the net acid excretion.

METABOLIC ALKALOSIS TREATMENT

Saline / Chloride responsive (Urine Cl <25 meq/L) Vomiting or nasogastric suction Diuretics Posthypercapnia Cystic Fibrosis Low chloride intake

Saline / Chloride un-responsive (urine Cl > 40 meq/L) Primary Mineralocorticoid excess Exogenous alkali load Barrter’s or Gitelman’s syndrome Severe Hypokalemia (K < 2.0)

Potassium must be repleted in all cases of Metabolic Alkalosis.

MIXED ACID BASE DISTURBANCES

Metabolic acidosis + Respiratory acidosisMetabolic acidosis + Metabolic alkalosisMetabolic acidosis + Respiratory alkalosisMetabolic alkalosis + Respiratory acidosisMetabolic alkalosis + Respiratory alkalosis

When to suspect a Mixed acid-base disorder???

1. The expected compensatory response does not occur

2. Compensatory response occurs, but level of compensation is inadequate or too extreme

3. Whenever the PCO2 and [HCO3-] becomes abnormal in the opposite direction. (i.e. one is elevated while the other is reduced). In simple acid base disorders, the direction of the compensatory response is always the same as the direction of the initial abnormal change.

4. pH is normal but PCO2 or HCO3- is abnormal

5. In anion gap metabolic acidosis, if the change in bicarbonate level is not proportional to the change of the anion gap. More specifically, if the delta ratio is greater than 2 or less than 1.

6. In simple acid base disorders, the compensatory response should never return the pH to normal. If that happens, suspect a mixed disorder.

6 STEPS FOR ACID BASE ANALYSIS

Step 1: Is there an Acidemia or Alkalemia?Step 2: Is the primary process metabolic or respiratory?

Step 3: If primary process is respiratory, is it acute or chronic?

Step 4: Is there an Anion gap? Na+ - Cl- - HCO3- > 12Step 5: Is the respiratory compensation adequate?

Expected pCO2 range = [1.5(measured HCO3-)] + 8 +/- 2

Step 6: Are there any other metabolic disturbances? Corrected HCO3- = (Measured HCO3-) + (AG – 12)

CASE STUDY 60 year old male presents to ED from a nursing home. You have no history

other than he has been breathing rapidly and is less responsive than usual.

Labs are:


Na 123 135 – 145 BUN 10 – 25

K 3.5 – 5 Cr 1.2 – 1.5

Cl 99 95 – 105 Glu 60 – 100

HCO3 5 22 – 26 pH 7.31 7.35 – 7.45

pCO2 10 35 – 45 PO2 80 – 100

Albumin 3.5 – 5


Na 123 135 – 145 BUN 10 – 25

K 3.5 – 5 Cr 1.2 – 1.5

Cl 99 95 – 105 Glu 60 – 100

HCO3 5 22 – 26 pH 7.31 7.35 – 7.45

pCO2 10 35 – 45 PO2 80 – 100

Albumin 3.5 – 5

Step 1: Is there an Acidemia or Alkalemia?Step 2: Is the primary process metabolic or respiratory?Step 3: If primary process is respiratory, is it acute or chronic?Step 4: Is there an Anion gap? Na+ - Cl- - HCO3- > 12Step 5: Is the respiratory compensation adequate?

Expected pCO2 range = [1.5(measured HCO3-)] + 8 +/- 2

Step 6: Are there any other metabolic disturbances?Corrected HCO3- = (Measured HCO3-) + (AG – 12)

Thanks for your Patience!!

Healthcare

Metabolic Acid Base Disturbances