Acid Base Disorders הפרעות בסיס חומצה Karl Skorecki Tel: asterisk indicates optional 2. you may contact me as noted above with questions

Hey- What’s the peeH here anyway?

Definitions and Equations 1.Medical definition of acid-base status of a patient refers to [H + ] of the extracellular fluid. 2. Normal [H + ] ECF is 40nM/Litre (equivalent to pH 7.40) 3. Acidemia is a state wherein the [H + ] ECF > 40 (pH < 7.40) Alkalemia is a state wherein the [H + ] ECF 7.40) (Euphemia is a state wherein the [H + ] ECF is normal).

Definitions and Equations (Cont.) 4. H + + HCO 3 - H 2 CO 3 H 2 O+CO 2 40nM 25mM PCO 2 = 40mmHg Acidosis  any process which increases PCO 2 /HCO 3 - ratio Alkalosis  any process which decreases PCO 2 /HCO 3 - ratio 5. The ratio PCO 2 /HCO 3 determines the [H + ] (pH) PCO 2 mmHg HCO 3 mmol/L H + nmol/L=25

Definitions and Equations (Cont.) H + = 25 PCO 2 HCO 3 6. Acidosis Alkalosis increases PCO 2 /HCO 3 ratio Metabolic: by lowering HCO 3 Respiratory: by raising PCO 2 decreases PCO 2 /HCO 3 ratio Metabolic: by raising HCO 3 Respiratory: by lowering PCO 2

הצעת חוק בסיסי החומצה שם החוק: חוק איסור השימוש ב-”Base Excess” וחוק איסור שימוש בשמות הנדרסון, הסלבך. הואיל וסטודנטים לרפואה בישראל כבר מספיק מסכנים ומבולבלים והואיל ואין מרצה או פרופסור בעולם שמבינ/ה בעצמו/ה את המונחים הנ"ל הצעת חוק זו באה לאסור לחלוטין את השימוש במונחים הנ"ל בכתב בעל-פה, במצגת, בביקור רופאים, בבית, בעבודה, ובכל מקרה (למעט בהצעת החוק הנוכחית) עונש: המפר את החוק לא יוכל לעשות רוטציה בשום מחלקה לנפרולוגיה המכבדת את עצמה, ויחוייב ללמוד את נושא בסיסי החומצה אך ורק במסגרת המחלקות הכירורגיות. נערך ונחתם היום ע"י השר לענייני בסיסי חומצה מדינת ישראל *

Definitions and Equations (Cont.) H + = 25 PCO 2 HCO 3 7. The four primary acid-base disturbances are: Metabolic acidosis (primary decrease in HCO 3 ) Metabolic alkalosis (primary increase in HCO 3 ) Respiratory acidosis (primary increase in PCO 2 ) Respiratory alkalosis (primary decrease in PCO 2 ) 8.- Can have none, one, two, or three of the above in combination. - Can have any combination except? - The net result can leave [H + ] normal/high (acidemia) or low (alkalemia)

Metabolic Acidosis 15 year-old with three week history of polyuria, polydipsia and 2 day history of nausea, abdominal pain, and weakness progressing to extreme drowsiness. Physical exam remarkable for rapid breathing, low blood pressure, and decreased level of consciousness. Lab: Glucose 220 [H + ] 62.5 (pH 7.2) PCO 2 25 HCO 3 10 Na K Cl - 105

H + = 25 PCO 2 HCO 3 Metabolic Acidosis (Cont.) BUT : HCO 3 is low PCO 2 is also low [H + ] is high (low pH; patient is acidemic) Metabolic acidosis  primary decrease in HCO 3 Maybe the patient has a metabolic acidosis What about the  PCO 2 ?

“Compensation” Rules Each primary acid base disturbance is associated with an expected compensation If the primary disturbance is metabolic (HCO 3 ), the expected compensation is respiratory (PCO 2 ) If the primary disturbance is respiratory (PCO 2 ), the expected compensation is metabolic (HCO 3 ) The compensation “tries” to restore the H + (pH) toward normal, but never quite makes it (why ?  see later) The “expected” amount of compensation is different for each of the four primary acid-base disturbances and needs to be memorized The direction of the expected compensation is always in the same direction as the primary disturbance

Metabolic Acidosis H + = 25 PCO 2 HCO 3  compensation  primary

Metabolic Alkalosis H + = 25 PCO 2 HCO 3  compensation  primary

Respiratory Acidosis H + = 25 PCO 2 HCO 3  primary  compensation

Respiratory Alkalosis H + = 25 PCO 2 HCO 3  primary  compensation

15 year-old with diabetic coma H (pH 7.2), PCO 2 25, HCO 3 10 H + = 25 PCO 2 HCO If primary metabolic acidosis, does the decrease in PCO 2 represent an “appropriate” expected compensation ? Metabolic acidosis: Rule: for every decrease of 1 mmol/Litre in HCO 3 there should be a decrease of 1 mmHg PCO 2 Did this happen ?

H + = 25 PCO 2 HCO pH = 7.2  HCO 3  = 15  PCO 2  = 15 Therefore : Respiratory compensation is appropriate

If respiratory compensation is appropriate, WHY is the patient still acidemic (p = 7.2) ? After all, most people could hyper-ventilate further, even down to PCO 2 of < 10 Answer: *

The capacity for “respiratory compensation” is what makes the bicarbonate buffer system so useful, even though the pK for is 6.8 (far from 7.4) H 2 CO 3 HCO 3 - CO 2 *

H + = 25 PCO 2 HCO pH = 7.2  Perfectly compensated metabolic acidosis

 What if PCO 2 remained “normal” ? H + = 25 PCO 2 HCO  H + = 100  pH = 7.00  Metabolic acidosis + respiratory acidosis clinical example ?

 What if PCO 2 fell to 16 ? H + = 25 PCO 2 HCO  H + = 40  pH = 7.4  Metabolic acidosis + respiratory alkalosis clinical example ? Extracellular pH looks good, but patient is very sick

Steps in Assessment of Metabolic Acidosis Step 1 : Is metabolic acidosis present ?  HCO 3 low and PCO 2 low (also occurs in respiratory alkalosis)  But patient acidemic Step 2 : Is the respiratory compensation…  as expected (  PCO 2 :  HCO 3 = 1:1)  too much (  PCO 2 :  HCO 3 > 1:1) (then also respiratory alkalosis)  too little (  PCO 2 :  HCO 3 < 1:1) (then also respiratory acidosis) Step 3 : Differential diagnosis “anion gap”

Metabolic Acidosis 15 year-old with diabetic coma and metabolic acidosis H PCO 2 25 K HCO 3 10 Na Cl Anion Gap = [Na + ] - ([Cl - ] + [HCO 3 - ]) = ( ) = 27 So what ?

Differential Diagnosis of Metabolic Acidosis “anion gap” Metabolic acidosis results from decrease in HCO 3 - There are two ways whereby  HCO 3 - (a) titration of HCO 3 - by an acid e.g. H + Ac + Na + HCO 3 -  NaAc + H 2 O + CO 2 (b) loss of NaHCO 3 in urine or stool Process (a) and process (b) leave different “imprints” in the plasma chemistries

Process A  titration of HCO 3 - by an acid H + X - + NaHCO 3 -  NaX + H 2 O + CO 2 Designate Na +, Cl -, and HCO 3 - as electrolytes whose concentrations we chose to measure Normally: Na + - (Cl - + HCO 3 - ) = “anion gap” ( ) = 12 Process A: We do not routinely measure X - (we don’t know what it is at the beginning) Therefore, for every “X - ” gained, there is one “HCO 3 - ” lost Therefore, “anion gap” will rise by one for every HCO 3 titrated away

Metabolic Acidosis 15 year-old with diabetic coma and metabolic acidosis H PCO 2 25 HCO 3 10 Na K Cl Anion Gap = 27 Normal anion gap is 12  anion Gap is = 15 HCO 3 - has decreased by = 15  Gap =  HCO 3 - Therefore : anion gap type metabolic acidosis

Anion Gap Metabolic Acidosis Only 4 categories: Ketoacidosis- Diabetic - Alcoholic - Starvation Lactic- Type A (ischemia, anoxia) - Type B (metabolic) Uremic Poisons- Methanol - Ethylene glycol - Salicylic acid - Other

Metabolic Acidosis 15 year-old with diabetes, coma and extensive vomiting H (pH 7.2) PCO 2 25 HCO 3 10 Na K Cl - 95 Anion Gap = ( ) = 37  Gap = 25  HCO 3 - = 15 How can that be ?

Answer: Occult metabolic alkalosis If no metabolic acidosis, HCO 3 would have been 35 Metabolic acidosis is much more severe than reflected in HCO 3 of 10 (35  10 Vs. 25  10) Consistent with vomiting More on metabolic alkalosis and vomiting after lunch

Metabolic Acidosis Anion Gap Ketoacidosis Lactic Uremic Poison Non-Anion Gap Rare: HCl poisoning Primary loss of HCO 3 - renal - complicated external (diarrhea, uretero-sigmoidostomy)

42 year-old presents with a 5-day history of severe watery diarrhea beginning 10 days after completing antibiotics for pyelonephritis H (pH 7.2) PCO 2 25 HCO 3 10 Na K Cl Anion gap ( ) = 12

Why doesn’t the anion gap rise in a non-anion gap acidosis? Anion gap = Na + - (Cl - + HCO 3 - ) By definition, the HCO 3 - has decreased. Therefore, if the anion gap hasn’t changed: Either the Na + has decreased Or, the Cl - has increased Answer : The Cl - rises (hyperchloremic metabolic acidosis) *

How does the Cl - know to increase ? Anion gap = Na + - (Cl - + HCO 3 - ) In a non-anion gap metabolic acidosis there is either:  Gain of HCl (rare HCl poisoning) So each HCO 3 - lost is accompanied by a Cl - gained Therefore no change in anion gap  Primary loss of Na + with HCO 3 - So each HCO 3 - lost is accompanied by a Na + lost If the Na + really decreased 1:1 with the HCO 3 -, then the anion gap wouldn’t change But, that doesn’t happen (the body defends its volume and osmolality and hates hypo Na + ) Therefore, the kidney reabsorbs Na + with Cl - and the Cl - increases *

Non Anion Gap (Hyperchloremic) Metabolic Acidosis HCl gain HCO 3 - loss  Extraneal  Renal Diarrhea Uretero-sigmoidostomy

Renal Acidosis Renal Vein Na + HCO 3 - 5,070mmol/day Na + HCO 3 - 5,000mmol/day Renal Artery NH 4 + Zero HCO 3 - Kidney’s Job: 1)Reclaim all of filtered HCO 3 - 2)Generate new HCO 3 - corresponding to HCO 3 - lost with dietary acid 3)Each new HCO 3 - generated corresponds to NH 4 + excreted

Renal Tubular Acidosis HCO 3 - 5,000 4,000 Proximal Failure to reclaim HCO 3 - genesis HCO 3 - 4,000 4,000 steady-state bicarbonaturia urine pH > 7 no bicarbonaturia urine pH < 6 Distal Failure to excrete H + (NH 4 + ) and hence generate HCO 3 -

Metabolic Acidosis 70 year-old with glaucoma treated with acetazolamide (carbonic anhydrase inhibitor) presents with weakness. Physical examination: BP 100/50 (baseline 150/90) H + 75 (pH 7.12) PCO 2 45 HCO 3 15 Na K Cl Anion gap 12 Urine pH 8 Bicarbonate low, patient very acidemic Respiratory compensation  respiratory acidosis Anion gap normal Diagnosis: acetazolamide  proximal RTA Hypokalemia  respiratory muscle weakness

Mixed Anion Gap + Non Anion Gap Metabolic Acidosis 70 year-old with glaucoma treated with acetazolamide (carbonic anhydrase inhibitor) presents with fever, severe abdominal pain (RUQ), jaundice and collapses. BP 60 systolic extremities; breathing: distressed. Lab: WBC 24,000 92% neutrophils H (pH 7.00) PCO 2 20 HCO 3 5 Na Cl Anion gap 22 Urine pH 8 Acid-base diagnosis: Likely scenario:

An anion gap metabolic acidosis can turn into a non-anion gap metabolic acidosis HOW ? If the anion accumulated in the plasma is excreted in the urine

Example: 15 year-old DKA treated with saline (isotonic NaCl) initial: H (pH 7.2; glucose 220) PCO 2 25 HCO 3 10 Na Cl Anion gap 27  gap = 15  HCO 3 = 15 Post Rx: H (pH 7.2) PCO 2 25 HCO 3 10 Na Cl Anion gap 18  gap = 6  HCO 3 = 15

Where have all the extra unmeasured anions gone ? Answer: Pissed away as a result of saline volume expansion Hint: Can measure gap in urine

The “Normal” or “Baseline” Anion Gap K + +Ca 2+ +Mg 2+ Na + Cl - HCO 3 gap albumin phosphate sulfate “unmeasured” 6 “measured” 140 “unmeasured” 18 “measured” 128 ALL CATIONS = ALL ANIONS Gap: Measured Cations (Na + ) - Measured Anions (Cl - + HCO 3 - ) Equals Unmeasured Anions - Unmeasured Cations Example : Hypoalbuminemia lowers the baseline anion gap *

Metabolic Acidosis Look at [H + ] (pH) HCO 3 - PCO 2 [H + ] high (pH low)  metabolic acidosis HCO 3 - low Look at PCO 2 to assess respiratory compensation Calculate anion gap Compare  anion gap to  bicarbonate H + = 25 PCO 2 HCO 3

pH [H + ] – not really necessary 1.Table on PALM 2.Between 7.25  7.50 for every deviation of one pH unit from 7.40, the [H + ] deviates correspondingly by 1mmol/litre in the opposite direction 3. Rule of 80% 7.00    8 X 80 =  8 X 64 =  8 X 50 =  8 X 40 =  8 X 32 =  8 X 26 = 21 *

Table [H + ] pH *

Causes of Metabolic Acidosis Inability to excrete the dietary H + load A.Diminished NH 4 + production 1. Renal failure 2. Hypoaldosteronism (type 4 renal tubular acidosis) B. Diminished H + secretion 1. Type 1 (distal) renal tubular acidosis Increased H + load or HCO 3 - loss A.Lactic acidosis B.Ketoacidosis C.Ingestions 1. Salicylates 5. Sulfur 2. Methanol or formaldehyde 6. Toluene 3. Ethylene glycol 7. Ammonium chloride 4. Paraldehyde 8. Hyperalimentation fluids D.Massive rhabdomyolysis E.Gastrointestinal HCO 3 - loss 1. Diarrhea 3. Ureterosigmoidostory 2. Pancreatic, billiary or intestinal fistulas4. Cholestyramine F.Renal HCO 3 - loss type 2 (proximal) renal tubular acidosis Most common causes shown in purple *

High anion gap A.Lactic acidosis: lactate, D-lactate B.Ketoacidosis:  -hydroxybutyrate C.Renal failure: sulfate, phosphate, urate, hippurate D.Ingestions 1. Salicylate: ketones, lactate, salicylate 2. Methanol or formaldehyde: formate 3. Ethylene glycol: glycolate, oxalate 4. Paraldehyde: organic anions 5. Toluene: hippurate (usually presents with anion gap) 6. Sulfur: SO 4 2- E.Massive rhabdomyolysis Anion Gap in Major Causes of Metabolic Acidosis The substances after the colon represent the major retained anions in the high anion gap acidosis *

Normal anion gap (hyperchloremic acidosis) Gastrointestinal loss of HCO Diarrhea Renal loss of HCO Type 2 (proximal) renal tubular acidosis C. Renal dysfunction 1. Some cases of renal failure 2. Hypoaldosteronism (type 4 renal tubular acidosis) 3. Type 1 (distal) renal tubular acidosis Ingestions: 1. Ammonium chloride 2. Hyperalimentation fluids E. Some cases of ketoacidosis, particularly during treatment with insulin Anion Gap in Major Causes of Metabolic Acidosis (cont.) *

H + = 25 PCO 2 HCO 3   Respiratory Acidosis Primary increase in PCO 2 (hypoventilation) The combination of increased PCO 2 and increased HCO 3 - can also be seen in metabolic alkalosis with respiratory compensation, but don’t be fooled because… In respiratory acidosis the compensation is metabolic and it takes time and can be divided into acute/chronic In metabolic acidosis the compensation is respiratory and occurs instantly Compensatory increase in HCO 3 (metabolic)

Metabolic Compensation for Respiratory Acidosis Primary Compensation  PCO 2  HCO 3 - Acute 10mmHg 1mmol/L Chronic 10mmHg 3mmol/L (memorize)

Mechanisms of Metabolic Response H+H+ Na+ H+H+ PCO 2 Enhanced HCO 3 reclamation

Causes of Respiratory Acidosis (Hypoventilation) Lungs Brain Chest wall + diaphragm Airway

Causes of Acute and Chronic Respiratory Acidosis Inhibition of the medullary respiratory center A.Acute 1. Drugs: opiates, anesthetics, sedatives 2. Oxygen in chronic hypercapnia 3. Cardiac arrest 4. Central sleep apena B. Chronic 1. Extreme obesity (Pickwickian syndrome) 2. Central nervous system lesions (rare) 3. Metabolic alkalosis (although hypercapnia is an appropriate response to the rise in pH in this setting) *

Causes of Acute and Chronic Respiratory Acidosis (cont.) Disorders of the respiratory muscles and chest wall A.Acute 1. Muscle weakness: crisis in myasthenia gravis, periodic paralysis, aminoglycosides, Guillain-Barré syndrome, severe hypokalemia or hypophosphatremia B. Chronic 1. Muscle weakness: spinal cord injury, poliomyelitis, amyotrophic lateral sclerosis, multiple sclerosis, myxedema 2. Kyphoscoliosis 3. Extreme obesity Upper airway obstruction A.Acute 1. Aspiration of foreign body or vomitus 2. Obstructive sleep apena 3. Laryngoispasm *

Causes of Acute and Chronic Respiratory Acidosis (cont.) Disorders affecting gas exchange across the pulmonary capillary A. Acute 1. Exacerbation of underlying lung disease (including Increased CO 2 production with high-carbohydrate diet) 2. Adult respiratory distress syndrome 3. Acute cardiogenic pulmonary edema 4. Severe asthma or pneumonia 5. Pneumothorax or hemothorax B. Chronic 1. Chronic obstructive pulmonary disease: bronchitis, emphysema 2. Extreme obesity Mechanical ventilation *

Lab: H + 60 (pH 7.22) PCO 2 68 HCO 3 28 PO year-old brought into ER because of found stuporous on the floor at home with an empty bottle of diazepam and a suicide note. Previously healthy. Physical examination: stuporous, but otherwise unremarkable. Patient acidemic with elevated PCO 2 and HCO 3  must at least have respiratory acidosis Compensation  PCO 2 28 appropriate for acute  HCO 3 3 respiratory acidosis

Lab: H (pH 7.00) PCO 2 68 HCO 3 17 Na + 138gap: (98+17) = 23 Cl - 98 K Creat 4.8 CK68,000 I.U. 28 year-old overdose has been lying on the floor for two days. Physical examination reveals extensive edema on the right side of the body. No urine in bladder Patient very acidemic, with high PCO 2 and low HCO 3 - Combined respiratory and metabolic acidosis Respiratory acidosis from drug overdose Expected compensation: HCO , but in reality: HCO   HCO 3  11 Anion gap 23:  gap = 11 Anion gap metabolic acidosis: rhabdomyalysis + renal failure

62 year-old with stable COPD Lab: H + 50 (pH 7.3) PCO 2 60 HCO 3 30 PO 2 60 Patient acidemic with elevated PCO 2 elevated bicarbonate Chronic respiratory acidosis Expected compensation:  PCO 2 20  HCO 3 6

62 year-old with stable COPD and 1-day history of worsening cough, fever and dyspnea with drowsiness Lab: H + 60 (pH 7.22) PCO 2 80 HCO 3 33 PO 2 45 Acute worsening of respiratory acidosis Expected compensation: Chronic  as before  HCO 3 to ~31 Acute  further smaller  HCO 3 to ~33 What is the most dangerous intervention, and if you make this mistake, what should you do ?

62 year-old with COPD and acute worsening reaches respiratory failure and is ventilated. ABG’s measured immediately after Lab: H + 30 (pH 7.5) PCO 2 40 HCO 3 33 PO What happened ? How will this affect weaning from ventilator ? What will her ABG’s look like if she extubates herself ?

62 year-old with COPD and respiratory failure on ventilator is treated with antibiotics and develops severe watery diarrhea Lab: H (pH 7.2) PCO 2 50 HCO 3 20 Na (gap 12) Cl Respiratory acidosis appropriately ventilated to PCO 2 50 Expected HCO 3 - is = 28 Observed HCO 3 - is 20 Therefore: Metabolic acidosis 28  20 Anion gap not elevated: antibiotic induced diarrhea

H + = 25 PCO 2 HCO 3   Primary decrease in PCO 2 (hyperventilation) Compensatory decrease in HCO 3 (metabolic) The metabolic compensation can be divided into acute (minutes) and chronic (hours to days) The compensation for chronic respiratory alkalosis is the most complete, and nearly normalizes the pH Respiratory Alkalosis The combination of low  PCO 2 and  HCO 3 was also seen in metabolic acidosis, but don’t be fooled, because…

Primary Compensation  PCO 2  HCO 3 - Acute 10mmHg 2mmol/L Chronic 10mmHg 5mmol/L (memorize) Metabolic Compensation for Respiratory Alkalosis

Low PCO 2 in proximal tubule Inhibition of Na + -H + exchanger Decreased proximal reabsorption of filtered HCO 3 - Bicarbonaturia It’s always easier to lose something then to win something – that’s why this compensation is so complete Mechanism for Metabolic Compensation

Causes of Respiratory Alkalosis Hypoxemia A.Pulmonary disease: pneumonia, interstitial fibrosis emboli, edema B.Congestive heart failure C.Hypotension or severe anemia D.High-altitude residence Pulmonary disease Direct stimulation of the medullary respiratory center A.Psychogenic or voluntary hyperventilation B.Hepatic failure C.Gram-negative septicemia D.Salicylate intoxication E.Postcorrection of metabolic acidosis F.Pregnancy and the lutheal phase of the menstrual cycle (due to progesterone) G.Neurologic disorders: cerebrovascular accidents, pontine tumors Mechanical ventilation *

After one week in hospital: H + 37 (pH 7.43) PCO 2 30 HCO year-old hypertensive man presents to ER with abrupt loss of consciousness and paralysis. Pex: hypertension, rapid breathing (hyperpnea), unresponsive, pinpoint pupils. CT reveales pontine hemorrhage Patient mildly alkalemic with low PCO 2 and low HCO 3, therefore: respiratory alkalosis Compensation  PCO 2  10 perfect compensation  HCO 3  5

Repeat ABG’s H + 28 (pH 7.52) PCO 2 20 HCO year-old man from previous slide has a bladder catheter and develops fever and WBC’s noted in urine Patient more alkalemic with further fall in PCO 2 by additional  10 and compensating further fall in HCO 3 by additional  2 Acute on chronic respiratory alkalosis

Repeat ABG’s and chemistry H + 50 (pH 7.30) PCO 2 20 HCO 3 10 Na Cl  20 (  8) 58 year-old man from previous slide now develops hypotension and shock L-lactate 8mmol/L Superimposed anion gap metabolic acidosis from septic shock lactic acidosis What if not aware of prior history and no prior ABG’s and given these values for the first time

H + 50 (pH 7.30) PCO 2 20 HCO 3 10 Na Cl  20 Patient acidemic with low bicarbonate  metabolic acidosis Expected PCO 2 25 Observed PCO 2 20 Therefore  respiratory alkalosis Anion gap 20  gap  8  Anion gap metabolic acidosis But  HCO 3 15 >  gap 8 Therefore: non anion gap metabolic acidosis or compensation for respiratory alkalosis

Repeat lab tests H (pH 7.00) PCO 2 40 HCO 3 10 Na (gap 20) Cl year-old man from previous slide experiences cardiopulmonary arrest. After some initial confusion he is intubated and ventilated. Why has pH dropped ? Essentially behaving as uncompensated metabolic acidosis Anion gap component: sepsis and lactate Non-anion gap component: “post compensation for respiratory acidosis”

Repeat values H + 40 (pH 7.40) PCO 2 40 HCO 3 25 Na Cl year-old man from previous slide with pontine hemorrhage, septic shock and ventilated, is given 3 ampules of NaHCO 3 for acidemia pH, PCO 2 and HCO 3 are normal Is there an acid-base disturbance ? Was it right to give this much bicarbonate ? Anion gap 25 What would have been the right treatment ?

Metabolic Alkalosis Probably the worst thing to have and most complicated to understand H + = 25 PCO 2 HCO 3   Primary increase in HCO 3 - Compensatory increase in PCO 2

Compensation Not very consistent or reliable Approximately: for every  1 HCO 3   0.7 PCO 2 What limits this compensation and how could you prove it?

Pathogenesis Complicated and variable Two major categories:  Boring  Interesting

Boring  Bicarbonate load to someone with no kidneys  converse: if renal function is normal, the presence of metabolic alkalosis severe (interesting) homeostatic disturbance

Pathogenesis of Interesting Metabolic Acidosis “Contraction” around HCO 3 - space KCl depletion states Volume expansion mineralo corticoid excess Volume contraction GI loss - vomiting - GI suction - chloridorrhea (rare) Diuretics - loop - thiazide

“Contraction” Around HCO 3 Space Normal 70Kg TBW 42L ECF 14L ICF 28L [HCO 3 ]25mmol/L10mmol/L HCO Total: 630

“Contraction” Around HCO 3 Space Heart failure: ECF expansion ECF 14  22L [HCO 3 - ] 25 Total 500 Treat with diuretics to  ECF ECF Litres [HCO 3 - ] 37 Shrink 7L 550/15 =

More to it! Diuretics also remove K + with Cl - Where does the K + come from ? Total body K + ICFECF 4 X 14 4,200meq 56meq [150] X 28 Patient on diuretic usually has a mmol K + deficit

Key Role of K + Cl - Depletion in Metabolic Alkalosis ICF Anion - K+K+ Cl - Na + ECF K + lost from ICF Cl - lost from ECF

H + + HCO 3 -  H 2 O + CO 2 K + Anion - H 2 O + CO 2  H 2 CO 3  H + + HCO 3 - K + lost in urine with Cl -  Gain of intracellular H + (intracellular acidosis) Gain of extracellular HCO 3 - (metabolic alkalosis) No  in total body buffer

Why do we care about acid-base disturbances ?  Clue to underlying disease But are they bad in their own right ? Answer: YES ! WHY ?

Main Reason: Metabolic acidosis Respiratory acidosis Metabolic alkalosis Intracellular acidosis

Intracellular Acidosis H + buffered in Histidines H+ H+  Met acidosis Resp acidosis met alkalosis histidine Intracellular protein function-conformation Changed conformation and function

Summary of Diuretic-Induced Metabolic Alkalosis 1. Contraction 2. K + depletion 3. Cl - depletion 4. Mineralocorticoid  secondary to volume depletion

Two Most Common Causes of Metabolic Alkalosis (with hypokalemia) 1.Diuretics (loop, thiazide) 2.Vomiting (GI suction)

Key Ion transport Protein in the Nephron *

Principal Cell *

Transport of Na + in the Principal Cell of the Cortical Collecting Duct *

Secretion of H + in the  Intercalated Cell of the Cortical Collecting Duct *

Secretion of HCO 3 - in the  Intercalated Cell of the Cortical Collecting Duct *

Key Ion transport Proteins Relevant to Metabolic Alkalosis  Cl - + HCO 3 - Reabsorbed proximally due to:  Volume  A II Luminal fluid  Cl -  HCO 3 1. Negative potential 2. Low Cl - 3. High K + favours H + secrection paradoxical acid urine  Aldo Na+ H + ATPase H + -K + ATPase Cl - -HCO 3 - exchanger *

Renal ion transport Derangements and Metabolic Alkalosis *

H + 31 (pH 7.49) PCO 2 55 HCO 3 45 PO year-old male smoker repeats reports one week of intractable profuse vomiting  PCO 2 and  HCO 3 - Metabolic alkalosis with respiratory compensation Respiratory acidosis with metabolic compensation

Two ways to figure out: 1.Calculate A-a O 2 gradient = PIO 2 – 1.25PCO 2 – P a O 2 = 150 – 69 – 68 = 13 Normal: lung disease not sufficient to cause chronic respiratory acidosis 2. Treat presumed metabolic alkalosis and expect PCO 2 to normalize (and PO 2 to rise)

Pathogenesis of Metabolic Alkalosis Diuretics Vomiting (or NG suction) H + Cl - NaCl + H 2 O + CO 2 Na + HCO 3 Na + HCO 3 - Normal H + Cl - to kidney Na + HCO 3 - Vomiting

Pathogenesis of Metabolic Alkalosis and Hypokalemia of GI Origin 1.HCl - loss accompanied by NaHCO 3 gain 2.Excess of NaHCO 3 excreted in urine 3.Equivalent to NaCl (volume) depletion 4.Hypovolemic stimulus to Na + reabsorption and aldosterone secretion 5.No Cl - to accompany Na + 6.Na + reabsorption accompanied by urinary excretion of H + and K +

Urine Electrolytes in Vomiting TimeNa + K + Cl - HCO 3 pH Days 1-3     > 6.8 Late      < 5.5 Low urine chloride is key K + loss in vomiting is urinary

Loss of hydrogen A.Gastrointestinal loss 1. Removal of gastric secretions - vomiting or nasogastric suction 2. Antacid therapy, particularly with cation-exchange resin 3. Chloride-losing diarrhea B.Renal Loss 1. Loop or thiazide-type diuretics 2. Mineralocorticoid excess 3. Postchronic hypercapnia 4. Low chloride intake 5. High-dose carbenicillin or other penicillin derivative 6. Hypercalcemia, including the milk-alkali syndrome C.H + movement into cells 1. Hypokalemia 2. Refeeding (?) Most common causes shown in blue Causes of Metabolic Alkalosis *

Retention of bicarbonate A.Massive blood transfusion B.Administration of NaHACO 3 C.Milk-alkali syndrome Contraction alkalosis A.Loop or thiazide-type diuretics B.Gastric losses in patients with achlorhydia C.Sweat losses in cystic fibrosis Causes of Metabolic Alkalosis (Cont.) *

A 63 year old man with a 15 year history of chronic obstructive lung disease developed ankle edema one year prior to admission and therapy was instituted with salt restriction, digoxin and furosemide. He complained of increasing weakness and drowsiness and was admitted for evaluation. On admission, the patient was slightly drowsy, cyanotic and in mild respiratory distress. The chest demonstrated the findings of chronic bronchitis and emphysema. There was no ankle edema and periods of bigeminal rhythm were confirmed by ECG. pH7.43 (H + 37)Sodium140 mmol/L Pco 2 70 mm HgPotassium 2.5 Po 2 50Chloride 74 HCO 3 46 mmol/L Urine: Sodium2 mmol/L Potassium 30 Chloride 1 * Acid – Base Diagnoses? Relation to potassium? Urine electrolytes?

The patient’s diuretic was discontinued, he was given supplemental KCl by mouth, and within four days his rhythm and ECG had normalized, and he felt stronger and more alert. Repeat evaluation showed: pH7.32Sodium140 mmol/L Pco 2 65 mm HgPotassium 4.4 Po 2 60Chloride 100 HCO 3 33 mmol/L * Is he better or worse now with the lower pH? What treatment helped him?

H + pH PCO 2 HCO 3 ___ Other________ gap 12, K gap 24, L-lactate PK + 1.9, UCl gap 21 Match Clinical Histories with Lab Results a.30 year old with Crohn’s disease and intestinal blind loop resumes enteral intake b.58 year old, dyspnea and hypotension after long air travel c.21 year old woman, BMI 19, amenorrhea, weakness d.28 year old status asthmaticus requiring intubation and sedation e.70 year old started one month ago on a new tablet to treat glaucoma

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Apetit! Bon *