ACID BASE BALANCE & REGULATION OF pH K HOMEOSTASIS

-6 EC [H+] ~ 40 nanomol/L Essential for normal renal function, When there is a change in [H+], proteins gain or lose H+ ions, resulting in Prot(-) + H(+)<---prot-H

alterations in charge distribution, molecular configuration, and protein function.

The process of H+ regulation involves 3 basic steps

Chemical buffering by the EC & IC buffers Control of the partial pressure of CO2 in the blood by alterations in the rate of alveolar ventilation Control of plasma HCO3 by changes in renal H+ secretion

 Under normal conditions, the steady state is preserved, as renal H+ secretion varies directly with the rate of H+ production Plasma [H+] and pH are maintained within narrow limits.
pH Arterial Venous 7.37 7.43 7.32 7.38 [H+]neq/L 37 - 43 42 48 Pco2,mmHg 36 44 42 50 [HCO3-],meq/l 22 - 26 23 - 27

 The kidneys must excrete the 50 to 100 meq of noncarbonic acid generated each day This is achieved by H+ secretion, although the mechanisms are different in the PT & TALH (Na H exchange) and in the CT (H-ATPase). The daily acid load cannot be excreted unless virtually all of the filtered HCO3 has been reabsorbed, because HCO3 loss in the urine is equivalent to adding H+ ions to the body Secreted H+ ions are excreted by binding to either filtered buffers, such as HPO4- & creatinine, or to NH3 to form NH4+. NH4+ is generated from the metabolism of glutamine in the PT; the rate of which this occurs can be varied according to physiologic needs. The extracellular pH is the primary physiologic regulator of net acid excretion. In pathophysiologic states, however, the effective circulating volume, aldosterone, & the plasma K+ concentration can all effect acid secretion, independent of the systemic pH.

 Oxidative metabolism produces CO2 (volatile acid) & H2O c.a. CO2 + H2O H2CO3 H(+) + HCO3(-)
Rate limiting step

Non volatile acids results from the metabolism of dietary protein, resulting in the accumulation of ~ 70 mmol acid per day Buffer systems prevent changes in pH
HCO3 / CO2 HPO4(2-) / H2PO4(-) Plasma & IC proteins, Hb Bone

H2CO3 ----- H(+) + HCO3(-) HCl ----- H(+) + Cl(-) NH4(+) ----- H(+) + NH3 H2PO4(-)----- H(+) + HPO4(2-) ACIDS: BASE carbonic acid noncarbonic acids

Law of mass action =

the velocity of a reaction is proportional to the product of the concentration of the reactants

H2O ----- H(+) + OH(-) v1 = k1 [H2O], v2 = k2 [H+] [OH-] At equilibrium v1 = v2 k1 [H2O] = k2 [H+] [OH-] K [H+] [OH-] K = k = [H2O] [H2O] ~ constant, Kw = [H+] [OH-] -14 (at body temp) = 2.4 x 10
V1/k1 V2/k2
1 2

pH
pH = - log [H+], = 7.40 Tightly regulated in the range 7.38 7.42 Relationship between arterial pH and [H+] in the physiologic range
pH
7.80 7.70 7.60 7.50 7.40 7.30 7.20 7.10 7.00 6.90 6.80

[H+] nmol/L
16 20 26 32 40 50 63 80 100 125 160

Henderson Hasselbalch equiation

[H+] = 24 X PCO2 [HCO3]

Role of the kidney

Accounts for reabsorption of some 85% of filtered bicarbonate, and operates at high capacity, but generates a low gradient of [H+] across the epithelium, with the luminal pH falling only slightly from 7.4 at the glomerulus to around 7.0 at the end of the PT. bicarbonate reabsorption also occurs at the CT, together with acid secretion

Net acid secretion

The tubules must secrete further acid into the tubular lumen beyond that needed to reabsorb all filtered bicarbonate Provide a buffer in the tubular fluid to assist in the removal of this acid Buffer: HPO4(2-), titratable acid NH3 / ammonia Net acid excretion =titratable acid + NH4(+) HCO3(-)

Stimulated by IC acidosis, and elevated Pco2

Bicarbonate secretion
In metabolic alkalosis HCO3- secretion by a second population of intercalated cells in CCT Polarity of the membrane transporters can be reversed
H+ H2O HCO3ClCA CO2 + OHATP

 Glutamine NH3+ glutamate(-) NH4(+) + -ketoglutarate(2-) Enzymes : glutaminase; & glutamate dehydrogenase NH4+ excretion can be increased
Increasing proximal NH4+ production from glutamine Lowering urine pH,which will increase NH3 diffusion into the lumen in the medullary CT

Titratable acidity
HPO4(2-) Minor: other weak acids ,such as creatinine, uric acid

Extracellular pH = major physiologic regulator of renal H+ secretion

Enhanced luminal Na-H exchange, by binding of H+ on the exchanger, and by synthesis of new exchangers Increased activity of Na-3HCO3 cotransporter in the basolateral membrane Increased NH4+ production from glutamine Alteration IC pH

Disturbances in acid base balance

Respiratory acidosis
Acute, Chronic

Metabolic acidosis, Respiratory alkalosis

Acute chronic

Metabolic alkalosis

Disorder

pH

[H+]

primary disturbance [HCO3]

compensatory response P CO2

Metabolic Acidosis Metabolic Alkalosis Respiratory Acidosis Respiratory Alkalosis

PCO2

[HCO3]

Primary disorder

Initial chemical change

Compensatory response

Compensatory Mechanism

Expected level of compensation

PCO2 = (1.5 [HCO3-]) + 8 2 Metabolic Acidosis HCO3PCO2 Hyperventilation PCO2 = 1.2 [HCO3-]

PCO2 = last 2 digits of pH

Metabolic Alkalosis Respiratory Acidosis HCO3PCO2 Hypoventilation PCO2 = (0.9 [HCO3-]) + 16 2 PCO2 = 0.7 [HCO3-] PCO2 HCO3[HCO3-] = 1 mEq/L for every 10 mm Hg PCO2 [HCO3-] = 3.5 mEq/L for every 10 mm Hg PCO2

Acute

Intracellular Buffering (hemoglobin, intracellular proteins) Generation of new HCO3- due to the increased excretion of ammonium. PCO2 HCO3-

Chronic Respiratory Alkalosis Acute

Intracellular Buffering

[HCO3-] = 2 mEq/L for every 10 mm Hg PCO2 [HCO3-] =4 mEq/L for every 10 mm Hg PCO2

Chronic

Decreased reabsorption of HCO3-, decreased excretion of ammonium

In acute respiratory acidosis, pH = 0.008 PCO2 In chronic respiratory acidosis, pH = 0.003 PCO2.

Compensatory Responses: summary 1. Compensatory responses never return the ph to normal or overshoot. 2. The basis of compensatory responses is to maintain the PCO2/[HCO3-] ratio. 3. Therefore, the direction of the compensatory response is always the same as that of the initial change. 4. Compensatory response to respiratory disorders is two-fold; a fast response due to cell buffering and a significantly slower response due to renal adaptation. 5. Compensatory response to metabolic disorders involves only an alteration in alveolar ventilation. 6. Metabolic responses cannot be defined as acute or chronic in terms of respiratory compensation because the extent of compensation is the same in each case.

Respiratory acidosis
Accumulation of CO2 in the body as a result of failure of pulmonary ventilation, hypercapnia
Lesion CNS (cerebral function, spinal cord) Peripheral nervous pathways involved in ventilation (peripheral nerve & muscle disorders) Lung disease involving impaired gas diffusion

This is initially buffered to a limited extend by IC buffers, such as Hb Over a few days, a new steady state is achieved;
renal excretion of net acid matches that being retained by the lungs Urine pH low, [HCO3] high

Acute respiratory acidosis

There is virtually no EC buffering, because HCO3(-) cannot buffer H2CO3 Renal response takes time to develop, the cell buffers, Hb and proteins, constitute the only protection against acute hypercapnia H2CO3 + Buf(-) HBuf + HCO3(-) Plasma [HCO3] will increase 1 meq/L for every 10 mmHg rise in PCO2.

Chronic respiratory acidosis

The persistent elevation in PCO2 stimulates renal H(+) secretion, resulting in the addition of HCO3 to ECF The net effect is that, after 3-5 days, a new steady state is attained, ~ 3.5 meq/L increase in plasma [HCO3] for every 10 mmHg increment in the PCO2 The rise in plasma [HCO3] is determined solely by the increase in renal H(+) secretion

Alveolar Arterial Oxygen Gradient

Calculation of the A-a oxygen gradient may be useful in differentiating intrinsic pulmonary disease from extrapulmonary disorders as the cause of hypercapnia The sum of the partial pressures of the other gasses in the alveolus must be equal to 150 mmHg, i.e. to the partial pressure of oxygen in the inspired air, PIO2. (A-a) O2 gradient = PIO2 1.25PaCO2 PaO2 A normal gradient essentially excludes intrinsic pulmonary disease; and suggest some form of central alveolar hypoventilation, or chest wall / ventilotory muscle abnormality The (A-a) O2 gradient is always increased in hypercapnic patients with intrinsic pulmonary disease

Metabolic Acidosis
Accumulation of non-volatile acids Inability of the kidneys to excrete the dietary H+ load or an increase in the generattion of H+, due to either the addition of H+ or to the loss of HCO3-

 Protective response
Physicochemical buffering of H(+) by available bases, HCO3, IC & EC proteins, tissue PO4; complete within a few min; further buffering in bone & other tissues over the ensuing hrs days The intracellular entry of H(+) is associated in part with the movement of K(+) out of the cell to maintain electroneutrality, especially if the MA are due to an excess of non-organic acids, such as in renal failure and diarrhea Respiratory response, the low pH acts as a potent stimulus to increase alveolar ventilation (stimulates the central & peripheral chemoreceptors ); manifest by a deep, rapid breathing pattern (kussmaul respiration) in 1-2 hrs, max level at 12-24 hrs, this response drives the CO2 below normal; provides a medium term compensation for the acidosis P(CO2) will fall 1.2 mmHg for every 1.0 meq/L reduction in plasma [HCO3] to a minimum P(CO2) of 10 15 mmHg Renal response, steady state correction requires the development over several days of an increased capacity by the kidney to excrete the metabolic acid load; this involves reabsorption of all fitered HCO3, maximum titration of filtered buffers with secreted H(+), and increased intrarenal synthesis of ammonia, which combines with the secreted hydrogen ions in the lumen and appears in the urine as ammonium Urine pH falls to a minimum (~4.5), and the plasma bicarbonate is elevated back up While the resulting pH is brought up towards normal, it never overshoots

 Principal factors causing an increase in H(+) secretion by the nephron

Increase in filtered load of bicarbonate result in increased Decrease in ECF volume Proximal bicarbonate
reabsorption

Decrease in plasma pH Increase in blood p(CO2) Hypokalemia Aldosterone

Decrease IC pH of the Tubular cells activates H(+) secretion and enhances NH3 synthesis. Enhances net acid secretion

Patterns of metabolic acidosis

HCl + NaHCO3 NaCl + H2CO3 CO2 + H2O, add HCl or loss HCO3HA + NaHCO3 NaA + H2CO3 CO2 + H2O, A- is the unmeasured anion Anion Gap / AG = [Na] ([Cl] + [HCO3]), normal 12+/-4, plasma protein (-) AG = unmeasured anions unmeasured cations the normal values should be adjusted downward for patients with hypoalbuminemia. correction is AG- 2.5 meq/l for every 1g/dl decline [plasma albumin] (nl = 4 g/dl). Delta ratio = Anion gap/ [HCO3-] or anion gap/ [HCO3-] = Measured anion gap Normal anion gap = AG - 12 Normal [HCO3-] Measured [HCO3-] 24-[HCO3] normally between 1 2 in an uncomplicated high AG metabolic acidosis < 1:1 suggest a combined high and normal AG acidosis > 2:1 suggest that the fall in plasma [HCO3] < expected due to concurrent metabolic alkalosis Osmolar Gap = Measured Posm Calculated Posm =10-15 mmol/L H2O Plasma osmolarity = 2(Na) + glucose/18 + BUN/2.8 The osmolar gap is increased in the presence of low molecular weight substances that are not included in the formula for calculating plasma osmolarity. Common substances that increase the osmolar gap are ethanol, ethylene glycol, methanol, acetone, isopropyl ethanol and propylene glycol. an elevated osmolar gap is a relatively nonspecific finding that is also commonly seen in alcoholic and diabetic ketoacidosis, lactic acidosis and in chronic renal failure, is thought to be due in part to elevations of endogenous glycerol, acetone, acetone metabolites, and in the case of renal failure, retention of unidentified small solutes.

A 44 year old moderately dehydrated man was admitted with a two day history of acute severe diarrhea. Electrolyte results: Na+ 134, K+ 2.9, Cl- 108, HCO3- 16, BUN 31, Cr 1.5. ABG: pH 7.31 pCO2 33 mmHg HCO3 16 pO2 93 mmHg What is the acid base disorder? Answer (using the step by step approach) 1. History: Based on the clinical scenario, likely acid base disorders in this patient are: Normal anion gap acidosis from diarrhea or Elevated anion gap acidosis secondary to lactic acidosis as a result of hypovolemia and poor perfusion. 2. Look at the pH. The pH is low, (less than 7.35) therefore by definition, patient is acidemic. 3. What is the process? Look at the PCO2, HCO3- . PCO2 and HCO3- are abnormal in the same direction, therefore less likely a mixed acid base disorder. Need to distinguish the initial change from the compensatory response. A low PCO2 represents alkalosis and is not consistent with the pH. A low HCO3- represents acidosis and is consistent with the pH, therefore it must be the initial change. The low PCO2 must be the compensatory response. Since the primary change involves HCO3-, this is a metabolic process, i.e. Metabolic Acidosis. 4. Calculate the anion gap The anion gap is Na - (Cl + HCO3-) = 134 -(108 + 16) = 10 Since gap is less than 16, it is therefore normal. 5. Is compensation adequate? Calculate the estimated PCO2. Using Winter's formula; PCO2 = 1.5 [HCO3-]) + 8 2 = 1.5 16 + 8 2 = 30-34. Since the actual PCO2 falls within the estimated range, we can deduce that the compensation is adequate and there is no seperate respiratory disorder present. Assessment: Normal anion gap acidosis with adequate compensation most likely secondary to severe diarrhea.

A 50 year old insulin dependent diabetic woman was brought to the ED by ambulance. She was semi-comatose and had been ill for several days. Current medication was digoxin and a thiazide diuretic for CHF. Lab results Serum chemistry: Na 132, K 2.7, Cl 79, HCO3- 19 Glu 815, Lactate 0.9 urine ketones 3+ ABG: pH 7.41 PCO2 32 HCO3- 19 pO2 82 What is the acid base disorder? Answer (using the step by step approach) 1. History: Based on the clinical scenario, possible acid base disorders in this patient are: Elevated anion gap acidosis secondary to DKA Metabolic alkalosis in the setting of thiazide diuretics use. 2. Look at the pH. Note that the pH is normal which would suggest no acid base disorder. But remember, pH may be normal in the presence of a mixed acid base disorder. 3. What is the process? Look at the PCO2, HCO3- . PCO2 is low indicating a possible respiratory alkalosis. The HCO3- is also low indicating a possible metabolic acidosis. Because the pH is normal, we are unable to distinguish the initial, primary change from the compensatory response. We suspect however that the patient has DKA, and therefore should have a metabolic acidosis with an anion gap that should be elevated. We can confirm this by calculating the anion gap. 4. Calculate the anion gap The anion gap is Na - (Cl + HCO3-) = 132 -(79 + 19) = 34 ... Metabolic acidosis why is the pH normal? If the patient has metabolic acidosis, we suspect a low ph unless there is another process acting to counteract the acidosis, i.e alkalosis. 5. To rule out a metabolic alkalosis, let us check the delta ratio. Delta ratio = Anion gap = (AG - 12) = (34 - 12) = 22 = 4.4 [HCO3-] (24 - [HCO3-]) (24 - 19) 5 delta ratio >2, there is a concurrent metabolic alkalosis. This is likely due to to the use of thiazide diuretic. Note that DKA is often associated with vomiting, but in this case;vomiting was not mentioned. Another possibility is a pre-existent high HCO3- level due to compensated chonic respiratory acidosis. But we have no reason to suspect chronic respiratory acidosis based on the history. Assessment: Mixed elevated anion gap metabolic acidosis and metabolic alkalosis likely due to DKA and thiazide diuretics.

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. Labs : Serum chemistry: Na 132, K 5.0, Cl 104, HCO3- 16 , BUN 25, Cr 1.3, Glu 75 ABG: pH 7.30, PCO2 29, HCO3- 16, PO2 92 Serum albumin 1.0 Does the patient have an abnormal anion gap? Answer The patient is acidemic with a low bicarb and low PCO2, suggesting metabolic acidosis. The patient is hyponatremic with a history of nausea, vomiting and poor intake. In this scenario, the metabolic acidosis may either be due to normal anion gap acidosis secondary to vomiting and/or lactic acidosis, ketoacidosis secondary to extreme volume loss and poor intake. To rule out lactic acidosis and ketoacidosis, we need to calculate the anion gap. Anion gap = (Na-(Cl +HCO3-) = 132 -(104 +16) = 12 Note that the anion gap appears to be normal, and thus lactic acidosis appears unlikely. However, note also that the patient is severely hypoalbuminemic with a serum albumin of 1.0. Because the anion gap is primarily determined by negatively charged plasma proteins such as albumin, we must adjust the normal value of the anion gap to more accurately reflect the albumin deficiency. 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) Therefore in this scenario, the normal anion gap should be: Decline in albumin = 4 - 1 = 3 g/dl Reduction in normal anion gap = 3 2.5 = 7.5 Adjusted anion gap = 12 - 7.5 = 4.5. Note now that a calculated anion gap of 12 is high when compared to the adjusted anion gap of 4.5 . Assessment: This patient has an elevated anion gap metabolic acidosis which may be due to lactic acidosis or ketoacidosis.

hyperalimentation

c.a. inh.: acetazolamide

(RTA)

KULT

Paraldehyde, INH, Metformin

Alcoholic patients have a predisposition to a # forms of increase AG metab. acidosis; starvation ketosis, lactic acidosis, and intoxication by methanol or ethylene glycol. Where metab. Acidosis is associated with advanced renal failure, the cause is usually the accumulation of complex organic acids normally excreted by the kidneys, and the result is an increased AG

 Urine AG = ([Na] +[K]) [Cl], pos/nearO

= unmeasured anions unmeasured cations Major unmeasured urinary cation = NH4(+), 20-40 meq/L In normal AG metabolic acidosis, the excretion of NH4(+) [and of Cl(-)] to maintain electroneutrality should increase markedly , -20 to >-50 meq/L The acidosis in renal failure and RTA 1&4 is due to impaired H(+) & NH4(+) excretion, and the urinary AG retains its normal positive value patient with a hyperchloremic metabolic acidosis: A negative UAG suggests GI loss of bicarbonate (eg diarrhea), a positive UAG suggests impaired renal acidification (ie renal tubular acidosis). Two conditions in which the urinary AG cannot be used
High AG acidosis, e.g. ketoacidosis, the unmeasured ketoacid anions will counteract the effect of NH4(+), U-AG may be positive Volume depletion with avid Na retention U[Na]<25 meq/L; the decrease in distal Na delivery impairs distal acidification, the concurrent increase in Cl absorption prevents the excretion of NH4Cl and the development of a negative U-AG

Renal Tubular Acidosis

Metabolic acidosis results from diminished net tubular H+ secretion Not associated with accumulaton of any organic acid anion Normal Anion Gap Congenital / acquired

Type1/distal
Basic defect Decreased distal acidification

Type 2/proximal
Diminished prox. HCO3 reabsorption

type 4
Aldosteron deficiency/ resistance Usually <5.5

Urine pH during acidemia

Plasma [HCO3] untreated

> 5.5

Variable:>5.5 if above reabsorptive threshold; <5.5 if below

Usually 14 - 20 meq/L

May be below 10 meq/L

Usually above 15 meq/L

Fractional excretion <3% in adults, may reach 5 19 % HCO3 at normal [HCO3] in young children Diagnosis Plasma [K] Response to NaHCO3 or NH4Cl Usually reduced / normal elevated with voltage defect 1 2 in adults; 4 14 in children

> 15 20%

< 3%

Response to NaHCO3 Normal / reduced (urinary K wasting) 10 15

Measure plasma [Aldosterone] Elevated

Dose of HCO3 meq/kg/d to normalize plasma [HCO3] Nonelectrolyte complications

1 3, may require no alkali if hyperK corrected

Nephrocalcinosis & renal stones (hypercalciuria, hyperphosphaturia)

Rickets / osteomalacia / osteopenia

None

 Fractional Excretion HCO3

Indications Differentiate Proximal RTA from Distal RTA Requires that serum bicarbonate be normal Calculation FE-HCO3 = (uHCO3 x sCr) / (sHCO3 x uCr) Annotation Where FE-HCO3 is Fractional Excretion of Bicarbonate Where uHCO3 is urine bicarbonate Where sHCO3 is serum bicarbonate Where uCr is Urine Creatinine Where sCr is Serum Creatinine Interpretation FE-HCO3 <5%: Distal RTA FE-HCO3 >15%: Proximal RTA Assumes serum bicarbonate >20 meq/L

Hypocalcemia, vit D deficiency ifosfamide

Hereditairy, disorders of Calcium metabolism, associated with hyperK, marked volume depletion

RTA 1
Defect H(+)ATPase pump in the cortex or in the medulla A reduction in the cortical Na(+) reabsoption, diminishing the degree of luminal negativity and producing a voltage dependent defect. This will lead to a concurrent impairment in K(+) secretion, which is also driven in part by the favorable electrical gradient. Hyperkalemia will accompany the metabolic acidosis. E.g. with urinary tract obstruction, sickle cell ds. Increase in membrane permeability, which allows for back diffusion of H(+) ions. E.g. Amphotericine B
Urine [HCO3] x plasma [Creatinine]

FEHCO3 (%) =

X 100
Plasma [HCO3] x urine [Creatinine]

RTA 2
Proximal HCO3 reabsorption is reduced as is total HCO3 reabsorptive capacity Self-limiting disorder in which the plasma [HCO3] is usually between 14 & 20 meq/L Intact reabsorptive capacity of distal nephron 3 factors are of primary importance in proximal HCO3 reabsorpyion:
Na-H exchanger in the luminal membrane Na-K ATPase pump in the basolateral membrane that provide the energy for NHE by maintaining a low cell [Na] & therefore a favorable gradient for passive Na-entry into the cell The enzyme Carbonic Anhydrase which is located both in the cell and in the lumen

Phosphate wasting & hypophosphatemia, renal glucosuria, & aminoaciduria, hypocalcemia, hypouricemia

RTA 1 VS RTA 2
Response to raising the plasma HCO3 concentration with NaHCO3 (infused at a rate of 0.5 - 1.0 meq/kg/h). the urine pH remain constant in RTA1, will rise markedly in RTA2, if the reabsorptive threshold is exceeded incomplete RTA1, plasma HCO3 is normal; diagnosis by giving an acid load as NH4Cl, 0.1 g/kg, this should induce a 4-5 meq/L fall in plasma [HCO3] within 4-6H

urine pH willl remain above 5.5 in RTA1

But <5 in normal subjects

RTA 4
Aldosterne deficiency / resistance HyperK impairs NH4 production & excetion Most have underlying renal insufficiency

Signs & Symptoms

Increase in minute ventilation, hyperpnea, dyspnea.

Fall in pH< 7.0-7.2 predisposes to ventricular arrhythmias, and can reduce both cardiac contractility and the inotropic response to catecholamines.
Neurologic: range lethargy to coma related to pH in CSF, more prominent in respiratory acidosis. CO2 crosses BBB more rapidly Skeletal problems, due in part to release of Ca(2+)

HCO3 required to correct the acidemia

HCO3 def = HCO3space X HCO3 def/L Bicarbonat space is appoximately 60 % lean BW for mild to moderate metabolic acidosis Can reach 70% or more for [HCO3] below 10 meq/L e.g. 70 kg male, raise [HCO3] from 6 to 10; HCO3 def = 0.7 x body weight(kg) x (10-6) = 196 meq

 Increase in alveolar ventilation will produce a decrease in pCO2, with a resulting increase in plasma pH. Acute Respiratory Alkalosis within 10 min, H+ ions move from the cell nto the ECF, where they combine with HCO3 H(+) + HCO3(-) ----> H2CO3 These H+ ions are primarily derived from protin, phophate, & Hb buffers in the cell, and from an alkalemia induced increase in cellular lactic acid production. HBuf ----> H(+) + Buf(-)

Respiratory Alkalosis

Chronic Respiratory Alkalosis

In the presence of persistent hypocapnia, there is a compensatory decrease in renal H+ secretion that begins within 2 hrs, but is not complete for 2 or 3 days Manifested by HCO3 loss in urine and decreased urinary NH4 excretion Etiology: hypoxemia, pumonary ds, direct stimulation of the medullary respiratory center, mechanical ventilation Symptoms: increased irritability, lightheadedness, paresthesias, cramps, carpopedal spasm, ventricular & supraventricular arrhytmias

Case
A 5 year old child is brought to the emergency room in a stuporous condition. The only pertinent history is that he had been playing with a bottle of aspirin tablets earlier that day. Arterial pH = 7.48 , PCO2 = 20 mmHg, [HCO3-] = 16 meq/L (expected = 20) The most likely explanation is salicylate overdose & salicylate - induced metabolic acidosis

Metabolic Alkalosis
Increase in pH, [HCO3-], PCO2 Primary elevation [HCO3] is usually induced by H+ loss from the GI tract or in the urine These H+ ions are derived from the intracellular dissociation of H2CO3H(+) + HCO3(-) There will be an equimolar generation of HCO3- for each meq of H+ loss Administration HCO3, by H+ movement into the cells (hypoK, K out H in), and by certain forms of volume contraction (contraction alkalosis) Perpetuation of metabolic alkalosis requiresw an impairment in renal HCO3- excretion (reduction GFR, & filtered HCO3 load, elevation in tubular reabsorption)

Causes of metabolic alkalosis

Loss of hydrogen
GI loss: vomiting, nasogastric tube, chloride losing diarrhea Renal loss: loop / thiazide diuretic, mineralocorticoid excess, post chronic hypercapnia, low Cl intake, hypercalcemia H+ movement into the cell: hypokalemia, refeeding

Retention of bcarbonate
Massive blood transfusion Administration of HCO3 Milk alkali syndrome

Contraction alkalosis
Loop / thiazide diuretics Gastric losses in patients with achlorhydria Sweat losses in cystic fibrosis

Causes of impaired HCO3 excretion that allows metabolic alkalosis to persist

Decreased glomerular filtration rate
Effective circulating volume depletion Renal failure (usually associated with metabolic acidosis)

Increased tubular reabsorption

Effective circulating volume depletion Chloride depletion Hypokalemia hyperaldosteronism

 Symptoms
Asymptomatic Related to volume depletion Related to hypokalemia Neurologic abnormality in posthypercapnic alkalosis probably due to a sudden fall in PCO2

Diagnosis
Urine Chloride; Metabolic alkalosis is the major clinical setting in which Urine [Cl-] may be a more accurate estimate of volume status than the Urine [Na+] The urine [Cl-] may not be useful in patients who are unable to maximally conserve Cl because of a defect in tubular reabsorption, e.g. renal insufficiency, severe hypokalemia (plasma [K] < 2.0 meq/L)

Urine [Cl-] in patients with metabolic alkalosis

Less than 25 meq/L
Vomiting /nasogastric suction Diuretics (late) Posthypercapnia Cystic fibrosis Low Cl- intake Refeeding

Greater than 40 meq/L

Mineralocorticoid excess Diuretics (early) Alkali load, HCO3 or other organic anion Severe hypokalemia ([K] < 2.0 meq/L)

 Saline responsive alkalosis & saline resisitant alkalosis Hypovolaemic & normovolaemic (or hypervolaemic) metabolic alkalosis
Saline responsive Vomiting or nasogastric suction Diuretics Posthypercapnia Low Cl intake Saline resistant Edematous states Mineralocorticoid excess Severe hypokalemia Renal failure

 Saline responsive alkalosis

Can be reversed by administration of NaCl water This will lower [HCO3] in three ways
Reversal of the contraction component Removing the stimulus to renal Na retention, permitting NaHCO3 excretion in the urine Reverses distal Cl delivery, which will promote HCO3 secretion in the cortical CT

Effectiveness can be followed bedside by measuring the urine pH Urine [Cl-] will remain <25 meq/L until the Cl deficit is corrected Any K depletion should be corrected with KCl

Saline resistant alkalosis

Edematous states, heart failure, hepatic cirrhosis,
nephrotic syndrome
Most commonly due to diuretic therapy reduction in effective circulating volume & renal insufficiency can contribute to the inability to excrete the excess HCO3 Therapy: withholding diuretics if possible, acetazolamide, HCl, or dialysis

HCO3 excess = HCO3 space X HCO3 excess per liter = the amount of HCl required to normalize plasma [HCO3-] In metabolic alkalosis the HCO3 space is ~ 50% lean body weight E.g. 60kg patient [HCO3] = 40 meq/L; HCO3 excess = 0.5 x 60 x (40-24) = 480 meq This formula underestimates the acid requirement of a patient in a non steady state

 Mineralocorticoid excess
Characterized by mild volume expansion and a rate of urinary [Na] excretion eual to intake (due to aldosterone escape) The combination of hypokalemia & hyperaldosteronism that is responsible for perpetuation of the alkalosis Correction of hypokalemia allows for increased HcO3 excretion, & causes H+ ions to move out of the cell into the extracellular fluid

Severe hypokaleemia
Patients with metabolic alkalosis and hypovolaemia may be resistant to NaCl therapy in the presence of severe K depletion This defect in Cl conservation appears to be due to diminished distal Cl reabsorption If Cl reabsorption is impaired and the availability of K for exchange with Na is limited, then Na reabsorption must be accompanied by increased H+ secretion and HCO3- reabsorption

K Homeostasis

Cellular mechanisms of renal potassium transport: proximal tubule and thick ascending limb. A, Proximal tubule potassium reabsorption is closely coupled to proximal sodium and water transport. Potassium is reabsorbed through both paracellular and cellular pathways. Proximal apical potassium channels are normally almost completely closed. The lumen of the proximal tubule is negative in the early proximal tubule and positive in late proximal tubule segments. Potassium transport is not specifically regulated in this portion of the nephron, but net potassium reabsorption is closely coupled to sodium and water reabsorption. B, In the thick ascending limb of Henles loop, potassium reabsorption proceeds by electroneutral Na+-K+-2Cl- cotransport in the thick ascending limb, the low intracellular sodium and chloride concentrations providing the driving force for transport. In addition, the positive lumen potential allows some portion of luminal potassium to be reabsorbed via paracellular pathways [11]. The apical potassium channel allows potassium recycling and provides substrate to the apical Na+-K+-2Cl- cotransporter [12]. Loop diuretics act by competing for the Cl- site on this carrier.

Cellular mechanisms of renal potassium transport: cortical collecting tubule. A, Principal cells of the cortical collecting duct: apical sodium channels play a key role in potassium secretion by increasing the intracellular sodium available to Na+-K+-ATPase pumps and by creating a favorable electrical potential for potassium secretion. Basolateral Na+-K+-ATPase creates a favorable concentration gradient for passive diffusion of potassium from cell to lumen through potassium-selective channels. B, Intercalated cells. Under conditions of potassium depletion, the cortical collecting duct becomes a site for net potassium reabsorption. The H+-K+-ATPase pump is regulated by potassium intake. Decreases in total body potassium increase pump activity, resulting in enhanced potassium reabsorption. This pump may be partly responsible for the maintenance of metabolic alkalosis in conditions of potassium depletion [11].

Hypokalemia and magnesium depletion. Hypokalemia and magnesium depletion can occur concurrently in a variety of clinical settings, including diuretic therapy, ketoacidosis, aminoglycoside therapy, and prolonged osmotic diuresis (as with poorly controlled diabetes mellitus). Hypokalemia is also a common finding in patients with congenital magnesium-losing kidney disease. The patient depicted was treated with cisplatin 2 months before presentation. Attempts at oral and intravenous potassium replacement of up to 80 mEq/day were unsuccessful in correcting the hypokalemia. Once serum magnesium was corrected, however, serum potassium quickly normalized [14].

 Fractional Excretion of Potassium

FEK = (uK x sCr x 100) / (sK x uCr)

FEK <10%: Renal cause of Hyperkalemia FEK >10%: Extrarenal cause of Hyperkalemia May also be increased in Chronic Renal Failure

Transtubular Potassium Gradient (TTKG) TTKG = (Urine K+ x Serum Osm)/(Serum K+ x Urine Osm) Normal person 6-12
TTKG <2: Non Renal cause of Hypokalemia TTKG >3-5: Extrarenal cause of Hypokalemia TTKG >10 in hyperkalemia, Low TTKG in hyperkalemia suggest hypoaldosteronism, renal tubular defect

Physiologic basis of the transtubular potassium concentration gradient (TTKG). Secretion of potassium in the cortical collecting duct and outer medullary collecting duct accounts for the vast majority of potassium excreted in the urine. Potassium secretion in these segments is influenced mainly by aldosterone, plasma potassium concentrations, and the anion composition of the fluid in the lumen. Use of the TTKG assumes that negligible amounts of potassium are secreted or reabsorbed distal to these sites. The final urinary potassium concentration then depends on water reabsorption in the medullary collecting ducts, which results in a rise in the final urinary potassium concentration without addition of significant amounts of potassium to the urine. The TTKG is calculated as follows:

TTKG = ([K+]urine/(U/P)osm)/[K+]plasma
The ratio of (U/P)osm allows for correction of the final urinary potassium concentration for the amount of water reabsorbed in the medullary collecting duct. In effect, the TTKG is an index of the gradient of potassium achieved at potassium secretory sites, independent of urine flow rate. The urine must at least be isoosmolal with respect to serum if the TTKG is to be meaningful

Bicarbonate IV

 Major physiologic functions

Cell metabolism, protein & glycogen synthesis Ratio of [K+] in the cell and ECF is the major determinant of the resting membrane potential across the cell membrane

Distribution of K between cells and ECF

Hypokalemia
Decreased net intake, starvation, inadequate replacement after operation Increased entry into cell
Elevation in EC pH,alkalosis Increased availability of insulin Elevated -adrenergic activity Periodic paralyse, hypokalemia form Pseudohypokalemia Treatment of megaloblastic anemia with B12 / folic acid; or neutropenia with GM-CSF Hypothermia

Increased GI losses,vomiting diarrhea, villous adenoma Increased urinary losses

Diuretics, loop / thiazide, RTA Mineralocorticoid excess Increased flow to distal nephron Na reabsorption with a nonreabsorbable anion: vomiting, metabolic acidosis, penicillin derivatives Amphotericin B HypoMg Polyuria L-dopa

Increased sweat losses Dialysis K depletion

Increased entry into cells

Elevation in extracellular pH; H+ ions are
released from the cellular buffers and move into the extracellular fluid to minimize the elevation in pH. To preserve electroneutrality K+ (& Na+) enter the cell. The pasma [K] falls less than 0.4 meq/L per 0.1 unit increase in extracellular pH.This also happens with HCO3 administration

Increased availability of Insulin; insulin

increases the activity of the Na-K-ATPase pump. Elevated B-adrenergic activity; catecholamines promote K entry into the cell, a response mediated by B2-adrenergic receptors, involves increased activity of Na-K-ATPase

 Periodic paralyse (hyperK, hypoK, normokalemic forms)

Hypokalemic Periodic Paralyse may be familial (AD), or aquired (thyrotoxicosis). episodes can be precipitated by rest after excercise, carbohydrate meal, stress, administration of insulin, epinephrine. Attacks are associated with the sudden movement of K into the cell. Similar acute form of paralysis can be induced by barium poisoning; barium blocks the K-channels in the cells

 Treatment of anemia or neutropenia.

Associated with K uptake by the new cells.

Multiple transfusion with frozen, washed red blood cells;

these cells lose up to 50% of their K+ during storage. in the recipient, K moves rapidly into the cells.

Pseudohypokalemia;
K uptake by metabolically active cells after the blood has been drawn, e.g. acute myeloid leukemia, if the blood is allowed to stand for a prolonged period at room temperature.

Hypothermia
can lower the plasma [K] as a result of K entry into the cells.

Increased GI losses
Normally 3-6 L of gastric, pancreatic, biliary, and intestinal secretions are secreted into the gastrointestinal lumen each day. Almost all of this fluid are reabsorbed, as only 100-200 ml of water and 5-10 meq of K are lost in the stool. Each of these secretion contains K+. Loss of any of them can lead to K depletion vomiting, diarrhoea, intestinal fistulas / drainage, chronic laxative abuse, colonic secretions from villous adenoma, cholera, VIPoma syndrome.

Increased urinary losses

Loop & thiazide diuretics
Increased flow to distal nephron Enhanced secretion of aldosterone

Mineralocorticoid excess
Primary hyperaldosteronism: adenoma, carcinoma, hyperplasia Cushing Disease Congenital adrenal hyperplasia
17--hydroxylase def 17--hydroxylase def

Chronic use of mineralocorticoid: fludrocortison Hyperreninism

renal artery stenosis, renin secreting tumor

hypersecretion of deoxycocorticosterone, other mineralocorticoid, incl apparent mineralocorticoid excess (licorice) Bartter's syndrome

Mineralocorticoid excess
Stimulates reabsorption of Na+,& secretion of K+ & H+ (often with hypertension & hypernatremia [145]) Can lead to hypokalemia & metabolic alkalosis Initial Na retention is followed by spontaneous natriuresis, edema does not usually occur This phenomenon is referred to as Aldosterone Escape ( increse in BP & ANP) For hypokalemia to occur there must be adequate delivery of Na & water to the distal nephron

Primary hyperaldosteronism
Adenoma 60 %,hyperplasia most of remaining Plasma Renin Activity is typically reduced Hyperplasia
Central serotoninergic pathways (inhibition of aldosterone secretion by cyproheptadine) Increased sensitivity of the adrenal zona glomerulosa to Angiotensin II AD glucocorticoid suppressible hyperaldosteronism, chimeric gene containing the enzyme 11-hydroxylase in the ACTH sensitive zona fasciculata

Cushing Syndrome / glucocorticoid excess

Cortisol is produced in zona fasciculata under the influence of ACTH Hypercortisolism
Hypersecretion of ACTH ( pituitary adenoma, nonendocrine ACTH producing tumor) primary adrenal adenoma / carcinoma

Hypertension
PRA usually normal, or increased, not reduced as with aldosterone excess Cortisol induced increased sensitivity to endogenous pressors (AII)

Diagnosis
Autonomous hypersercretion of cortisol must be confirmed
Increased urinary free cortisol excretion in a 24 h urine collection Lack of adequate suppression of 24h urine hydroxycorticosteroid (to <4mg/d) after administration of 0.5mg dexamethasone q6h for 8 doses = the low dose dexamethasone suppression test

The specific cause: pituitary tumor vs adrenal adenoma vs ectopic ACTH production, can be identified my measuring plasma ACTH and cortisol levels
At 8 a.m. on 2 successive days, the second after administering 8mg (high dose) dexamethasone at 11 p.m. the previous night Before & after administratration of 2mg dexamethasone q6h for 8 doses = the high dose dexamethasone suppression test
Patients with adrenal disease have low to absent ACTH levels and cortisol secretion, that is not suppressed by dexamethasone. Next step should be CT / MRI Pituitary disease is associated with normal or elevated ACTH secretion, and both ACTH & cortisol are suppressed by >50% by dexamethasone ACTH levels are increased with ectopic production, is not suppressed by dexamethasone

If the results are equivocal, the response to an infusion of corticotrropin releasing factor (CRF) can be assessed; ACTH will rise by >50% and cortisol >20% with pituitary disease; unchanged with ectopic production

Patients with pituitary disease should undergo gadalinium-enhanced MRI to confirm the diagnosis and locate the tumor; bilateral inferior petrosal sinus sampling can be used to identify the affected side

Congenital adrenal hyperplasia

Deoxycorticosterone (DOC) & corticosterone are synthesized in the adrenal cortex, and have significant mineralocorticoid activity Secretion is regulated by ACTH, not AII / [K] When cortisol production is reduced because of enzyme def.,ACTH, DOC,& corticosterone will be persistently elevated Synthesis of aldosterone also impaired Glucocorticoid and [K] balance can be restored by administration of cortisol
Risk of inducing Na wasting & hyperkalemia Mineralocorticoid replacement with fludrocortisone may be required

Familial glucocorticoid resistance,

inherited abnormality in glucocorticoid receptor Cannot bind to cortisol Adrenal stimulation due to high ACTH levels

Syndrome of apparent mineralocorticoid excess

Licorice in chewing tobacco, candies, Steroid in licorice: glycyrrhetinic acid
Has sligh meneralocorticoid activity Impairs the action of enzyme 11-hydroxysteroid dehydrogenase that converts cortisol to cortisone in aldosterone target tissues

Hypertension, hypokalemia, and metabolic alkalosis

Other mineralocorticoids: DOC producing adenomas, Liddles syndrome:

Low renin & low aldosterone

Bartters syndrome
Hyperreninemia & hyperaldosteronism Hyperplasia juxtaglomerular apparatus Hypokalemic alkalosis Increased secretion of vasodilator prostaglandins (PG E & PC)
May partially explain the normal BP

Defect in NaCl reabsorption in TALH or DT Changes in Bartters syndrome ~ surreptious use of loop / thiazide diuretics

 Classic Bartters syndrome

Generally presents early in life, before age 6 Associated with retarded growth, mental retardation, polyuria, polidipsia, decreased concentrating ability, hypercalciuria, & plasma [Mg] that is normal / mildly reduced Defect medullary portion of the thick ascending limb; central role in creating countercurrent gradient required for urine concentration

Gitelmans syndrome
More benign, and usually diagnosed incidentally in late childhood / adulthood Mg wasting & hypomagnesemia (sometimes tetany) Calcium excretion tends to be reduced, hypocalciuria Concentrating ability is maintained suggesting intact function in the medullary thick limb Primary defect is in the cortical aspect of the thick ascending limb or in the distal tubule, the major site of active Mg & Ca reabsorption

Fall in NaCl reabsorption,Na & water loss volume depletion Enhanced renin secretion AII & aldosterone, Combination of increased distal flow & hyperaldosteronism promotes K+ secretion, and the development of hypokalemia, that may be exacerbated by concurrent hypomagnesemia. Prostaglandins directly increases renin release,also contribute to this process

Diagnosis of primary hyperaldosteronism

Should be suspected in any patient with hypertension & unexplained hypokalemia Occasionally, patients are normokalemic, or hypokalemic but normotensive 24h Urine collection for K+,
Diuretics must be discontinued prior to collection Important that the patient not be volume depleted The degree of K wasting can be enhanced by high Na diet Na-induced hypokalemia is strongly indicative of nonsuppressible hyperaldosteronism

Plasma renin activity Aldosterone secretion; plasma [aldosterone] or urinary excretion of aldosterone / metabolites
Low renin low aldosterone ~ nonaldosterone mineralocorticoid
Congenital adrenal hyperplasia, DOC producing tumor Licorice Liddles syndrome

Low renin high aldosterone >30 g/dl ~ hyperaldosteronism Diagnostic accuracy can be increased by attempting to suppress aldosterone production by giving 2 L NS IV over 4h
Normal, should fall to 6ug/dl or less Values >10 ug/dl are diagnostic Values between 6&10 are nondiagnostic; a more prolonged suppression test should be done; using high Na diet plus 0.6 -1.2 mg fludrocortisone for 3 days
Plasma [aldosterone] should be measured with the patient recumbent, off K supplements, Relative normokalemia

Potential confounding variables should be eliminated

 Adenoma vs hyperplasia
Usually hyperplasia is less severe Rise in [aldosterone] following assumption of the upright posture between 8 a.m. and noon
May reflect increased sensitivity of the zona glomerulosa to AII ~ hyperplasia Induces no change in [aldosterone] with an adrenal adenoma

CT scanning / MRI Measurement of adrenal vein aldosterone

Unilateral adenoma ~ > 10 fold increase in [aldosterone] on the side of the tumor To be certain that the samples are from the adrenal vein, an ACTH-stimulated [cortisol] should also be measured; roughly the same on both sites, but much greater in a peripheral vein

(131)I-iodocholesterol (precursor of aldosterone) scintillation scanning

Acid base disorders in hypokalemia

Metabolic acidosis

Loss of lower intestinal secretions Ketoacidosis RTA Salt wasting nephropathies

Diuretic therapy Vomiting / nasogastric suction Mineralocorticoid excess Penicillin derivatives

Metabolic alkalosis

Treatment
K deficit can only be approximated; there s no definite correlation between plasma [K+] and body K+ stores. In general, a reduction in [K] from 4 to 3 meq/L requires the loss of > 200 meq K+. An additional 200 400 meq def will lower the plasma [K+] to 2 meq/L Oral KCl IV KCl;
in most circumstances K+ 20-40meq (max 60 meq, if through a peripheral vein) is added to 1L of dextrose / saline solution The addition of that much K in a dextrose solution may lead to a transient reduction in the plasma [K+] of 0.2 1.4 meq/L Generally IV K+ is administered at a maximum rate of 10-20 meq/h

Hyperkalemia
Increased intake: oral, IV Movement from cells to ECF
Pseudohyperkalemia Metabolic acidosis Insulin deficiency & hyperosmolality in uncontrolled DM Acute hyperosmolality due to hypernatremia or hypertonic mannitol administration Tissue catabolism -adrenergic blockade Severe exercise Digitalis overdose Hyperkalemic periodic paralysis Cardiac surgery Succinylcholine Arginine Renal failure Effective circulating volume depletion Hypoaldosteronism RTA type I hyperkalemic form Selective K secretory defect

Decreased urinary secretion

Defense against hyperkalemia

Initial uptake of most of the excess K by the cells, mediated by insulin, 2-adrenergic receptors, and K+ itself Subsequent urinary K+ secretion of most of the excess K+ within 6-8h; the small elevation in plasma [K+] is responsible for this increase in K excretion, both directly and by increasing aldosterone release The ability to tolerate a K+ load is increased by the chronic ingestion of a high-K diet ~ K adaptation

 Pseudohyperkalemia; due to K+ movement out of the cells during or after the blood specimen has been drawn.
Mechanical trauma during venipuncture Measurement of the serum after clotting has occurred, e.g.in leukocytosis (>100,000/mm3), & thrombocytosis (serum [K+] rises 0.15meq/L for every100,000/mm3 elevation)

Increase in plasma osmolality;

pulls water out of the cells, leads to the parallel movement of K+ into the ECF
Loss of water raises [K] IC Solvent drag

Cardiac surgery;
Washout of ischemic areas that were underperfused Rewarming, hypothermia causes K to move into the cells

Succinylcholine;
Acts by depolarizing the cell membrane, cell interrior becomes less electronegative Favors movement of K+ ions out of the cell

Arginine HCl;
Cationic arginine enters the cell, & K+ out

 Renal failure; multiple factors

Too few nephrons Oliguria, decrease in flow to the distal secretory site Increased dietary K load Low [K] IC & impaired cellular uptake Decreased Na-K-ATPase

Effective circulating volume depletion;

Often associated with K depletion But impaired ability to handle K load
Reduction in urinary K secretion (distal flow) Reduced K entry into cells

Diagnosis of hypoaldosteronism
Discontinuation of any potensial offending drug,e.g. nsaids heparin, ACE-I, ARB, k-sparing diuretics, Measurement of morning plasma renin activity, aldosterone, cortisol To minimize confounding borderline values, give 2040mg furosemide at 6 pm & 6 am before blood drawing An indirect way to estimate the effect of aldoterone is to measure the tubular fluid [K+] at the end of the cortical collecting tubule; with the following assumptions
Uosm at this site ~ Posm equilibration with the isoosmotic interstitium will occur in the presence of ADH Little / no K secretion or reabsorption takes place in the medullary collecting tubule

Transtubular K+ gradient, TTKG = as long as U(Na)>25 meq/L

U(K+) / ( Uosm/Posm) P(K+)

 TTKG in normal subjects on a egular diet is 8 9, and rises to >11 with a K+ load indicating increased K secretion A value <7, particularly <5 in a hyperkalemic patient is highly suggestive for hypoaldosteronism E.g. U(K)=30meq/L, P(K)=6.5meq/L, Uosm=560 mosm/kg, Posm=280mosm/kg TTKG = 30/(560/280) =2.3 6.5

Type I RTA hyperkalemic form

Type I RTA, usually hypokalemia Na reabsorption occurs in exchange for K Hyperkalemia
Inability to reabsorb Na Impairs generation of lumen-negative potential difference Impairs H / K secretion

E.g.: obstructive uropathy, sickle cell disease,

Treatment
Antagonism of membrane action
Calcium Hypertonic Na solution (if hyponatremic)

Increased K entry into cells

Glucose & insulin NaHCO3 2-adrenergic agonists Hypertonic Na solutions (if hyponatremic)

Removal of K excess
Diuretics Cation exchange resins Dialysis

Hyponatremia increases the toxicity of hyperkalemia to the heart